REVIEW published: 01 June 2021 doi: 10.3389/fcell.2021.670273 New Insights Into the Role of Autophagy in Liver Surgery in the Setting of Metabolic Syndrome and Related Diseases Ana Isabel Álvarez-Mercado 1,2,3† , Carlos Rojano-Alfonso 4† , Marc Micó-Carnero 4 , Albert Caballeria-Casals 4 , Carmen Peralta 4* † and Araní Casillas-Ramírez 5,6* † 1 Department of Biochemistry and Molecular Biology II, School of Pharmacy, Granada, Spain, 2 Institute of Nutrition and Food Edited by: Technology “José Mataix”, Biomedical Research Center, Parque Tecnológico Ciencias de la Salud, Granada, Spain, William T. Festuccia, 3 Instituto de Investigación Biosanitaria ibs. GRANADA, Complejo Hospitalario Universitario de Granada, Granada, Spain, University of São Paulo, Brazil 4 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 5 Hospital Regional de Alta Reviewed by: Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria, Mexico, 6 Facultad de Medicina e Ingeniería en William K. K. Wu, Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros, Mexico Chinese University of Hong Kong, China Shengmin Yan, Visceral obesity is an important component of metabolic syndrome, a cluster of diseases Tulane University, United States that also includes diabetes and insulin resistance. A combination of these metabolic *Correspondence: disorders damages liver function, which manifests as non-alcoholic fatty liver disease Carmen Peralta cperalta@clinic.cat (NAFLD). NAFLD is a common cause of abnormal liver function, and numerous studies Araní Casillas-Ramírez have established the enormously deleterious role of hepatic steatosis in ischemia- aranyc@yahoo.com reperfusion (I/R) injury that inevitably occurs in both liver resection and transplantation. † These authors have contributed Thus, steatotic livers exhibit a higher frequency of post-surgical complications after equally to this work hepatectomy, and using liver grafts from donors with NAFLD is associated with an Specialty section: increased risk of post-surgical morbidity and mortality in the recipient. Diabetes, another This article was submitted to Cellular Biochemistry, MetS-related metabolic disorder, also worsens hepatic I/R injury, and similar to NAFLD, a section of the journal diabetes is associated with a poor prognosis after liver surgery. Due to the large increase Frontiers in Cell and Developmental in the prevalence of MetS, NAFLD, and diabetes, their association is frequent in the Biology population and therefore, in patients requiring liver resection and in potential liver graft Received: 20 February 2021 Accepted: 23 April 2021 donors. This scenario requires advancement in therapies to improve postoperative Published: 01 June 2021 results in patients suffering from metabolic diseases and undergoing liver surgery; and Citation: in this sense, the bases for designing therapeutic strategies are in-depth knowledge Álvarez-Mercado AI, Rojano-Alfonso C, Micó-Carnero M, about the molecular signaling pathways underlying the effects of MetS-related diseases Caballeria-Casals A, Peralta C and and I/R injury on liver tissue. A common denominator in all these diseases is autophagy. Casillas-Ramírez A (2021) New In fact, in the context of obesity, autophagy is profoundly diminished in hepatocytes Insights Into the Role of Autophagy in Liver Surgery in the Setting and alters mitochondrial functions in the liver. In insulin resistance conditions, there is of Metabolic Syndrome and Related a suppression of autophagy in the liver, which is associated with the accumulation of Diseases. Front. Cell Dev. Biol. 9:670273. lipids, being this is a risk factor for NAFLD. Also, oxidative stress occurring in hepatic doi: 10.3389/fcell.2021.670273 I/R injury promotes autophagy. The present review aims to shed some light on the role Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome of autophagy in livers undergoing surgery and also suffering from metabolic diseases, which may lead to the discovery of effective therapeutic targets that could be translated from laboratory to clinical practice, to improve postoperative results of liver surgeries when performed in the presence of one or more metabolic diseases. Keywords: autophagy, metabolic syndrome, ischemia-reperfusion, liver surgery, transplantation INTRODUCTION The complex molecular interrelation between obesity, MetS, insulin resistance, and diabetes does not allow us to clarify Obesity is the major risk for the development of metabolic which is the precise concatenation of events driving NAFLD. syndrome (MetS), a prevalent entity in Western societies However, a common denominator in all of such metabolic that includes cardiovascular risk factors i.e., hypertension, diseases is autophagy. Abnormal autophagy fails to restore diabetes mellitus, and, insulin resistance (Nakao et al., 2012). homeostasis, promotes the development of obesity-associated The combination of these metabolic disorders compromises diseases, and increases insulin resistance (Yang et al., 2010). The liver function, manifested as non-alcoholic fatty liver disease pathophysiology of diabetes mellitus types I and II, as well as (NAFLD), a risk marker in type 2 diabetes (T2D) and MetS. β-cell dysfunction, has been associated with abnormal autophagy NAFLD compromises pre-existing hepatic disease and is mechanisms (Gonzalez et al., 2011). Abnormal autophagy may progressively on the rise throughout the world (Gadiparthi also underlie I/R injury and NAFLD in partially resected or et al., 2020). Albeit controversial, the use of fatty livers in transplanted livers (Zhao et al., 2016). Moderate I/R injury liver transplantation is also increasing due to the paucity causes cell dysfunction by autophagy and activates survival of available organs, but they tend to poorly tolerate the recovery systems, but prolonged I/R-mediated cell damage ischemia/reperfusion (I/R) process, leading to primary non- may lead to apoptosis and necrosis (Lopez-Neblina et al., function, early graft dysfunction, and graft loss. Significant 2005; Zhu J. et al., 2016; Ling et al., 2017). Furthermore, steatosis has also been more frequent in tumor-associated hyperglycemia exacerbates liver ischemic injury (Behrends et al., hepatic resections in which I/R is also sub-par, and carries 2010). Patients with diabetes and requiring a liver resection high morbidity in the immediate postoperative period are at great risk of hepatic injury during surgery (Han (Micó-Carnero et al., 2021). et al., 2014), and this also applies to potential liver transplant diabetic donors. Due to the great increase in the prevalence Abbreviations: ADP, adenosine diphosphate; AGE, advanced glycation end of NAFLD and diabetes, their association is frequently present product; Akt, serine-threonine protein kinase Akt; AMPK, adenosine 50 - in society and hence, in potential liver graft donors, and monophosphate-activated protein kinase; ASNS, asparagine synthetase; Atg, patients requiring a hepatic resection. This scenario requires autophagy gen; ATP, adenosine triphosphate; ATP6V1B2, vacuolar H + -ATPase, the development of effective strategies to improve post-operative B2 subunit; BNIP3, BCL2 and adenovirus E1B 19-kDa-interacting protein 3; CRY1, cryptochrome 1; CXCR3, chemokine (C-X-C motif) receptor 3; DNA, results in NAFLD and/or diabetic patients subjected to liver desoxyribonucleic acid; ER, endoplasmic reticulum; ERK, extracellular signal- surgery; hence, a thorough understanding of the signaling regulated kinase; FA, fatty acids; FGF21, fibroblast growth factor 21; FOXO, pathways in NAFLD, MetS, diabetes, insulin resistance, and I/R forkhead box O; GSK3b, glycogen synthase kinase 3 beta; HFD, high-fat diet; injury are paramount. HOTAIR, homeobox (HOX) transcript antisense RNA; I/R, ischemia/reperfusion; IKK, inhibitor of NF-κB kinase; IL, interleukin; IRE1, inositol-requiring Based on the previously presented challenges, we will enzyme 1; IRF1, interferon regulatory factor 1; IRGM, immunity-related specifically review the effects of obesity, MetS, insulin resistance, guanosine triphosphatase family M; IRS, insulin receptor substrate; JNK, c-Jun and/or diabetes in the postoperative outcomes from liver NH(2)-terminal kinase; LAMP, lysosome-associated membrane protein; LC3, microtubule-associated protein light-chain 3; LD, lipid droplets; lncRNAs, long- resection and transplantation, and the crucial role of autophagy non-coding RNAs; MAPK, mitogen-activated protein kinase; MC3R, melanocortin in that setting. A better understanding of the molecular 3 receptor; MCD, methionine/choline-deficient; MetS, metabolic sydrome; miR, mechanisms related to autophagy underlying such conditions microRNA; mTOR, mammalian target of rapamycin; mTORC1, mammalian is extremely relevant to develop effective therapeutic targets to target of rapamycin complex 1; NAD + , nicotinamide adenine dinucleotide; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; improve the post-operative outcomes of hepatic surgeries when NF-kB, nuclear factor kappa B; NIX, BNIP3-like (BNIP3L), also known as NIX; associated with the mentioned comorbidities. In this sense, it NLRP3, nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) is important the knowledge whether the autophagy process is family pyrin domain containing 3; NO, nitric oxide; NPC1, Niemann-Pick-type C1; PARP, poly (ADP-ribose) polymerase; PERK, protein kinase R (PKR)-like different in livers affected by metabolic comorbidities with and endoplasmic reticulum kinase; PGAM5, phosphoglycerate mutase family member without surgical intervention. Then, we will initially analyze 5; PI3K, phosphoinositide-3 kinase; PINK1, phosphatase and tensin homolog the effects of MetS and related diseases as obesity, insulin (PTEN)-induced putative kinase 1; PKC, protein kinase C; PLIN2, perilipin 2; resistance, NAFLD, and/or diabetes on livers without surgery, PPAR-γ, peroxisome proliferator-activated receptor gamma; RAGE, receptor for AGE; RBP4, retinol binding protein 4; RNA, ribonucleic acid; ROS, reactive and the involvement of the autophagy process in such context. oxygen species; Rubicon, run domain beclin-1-interacting and cysteine-rich We will then focus on how metabolic diseases negatively affect domain-containing protein; S6K1, ribosome S6 protein kinase 1; Sirt1, silencing hepatic I/R injury inherent to liver surgery. Finally, we will information regulator 1; SOD, superoxide dismutase; SQSTM, p62/sequestosome; present the mechanisms underlying the role of autophagy in SRA, class A scavenger receptor; T2D, type 2 diabetes; TFEB, transcription factor EB; TNF-α, tumor necrosis factor alpha; UPR, unfolded protein response; Vps34, damage in surgically intervened livers, especially those suffering vacuolar protein sorting 34. metabolic diseases. Frontiers in Cell and Developmental Biology | www.frontiersin.org 2 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome INVOLVEMENT OF HEPATIC cellular components (Jung et al., 2020). In addition, enhanced endoplasmic reticulum (ER) stress can deregulate lysosomal AUTOPHAGY IN THE EFFECTS OF acidification and thus, blocking autophagy in hepatocytes (Chen METABOLIC DYSFUNCTIONS ON THE et al., 2019a). This provokes hepatotoxicity, cell death, and LIVER alteration of hepatic function (Jung et al., 2020). A close association between autophagy functionality, obesity, and liver Autophagy is a vacuolar self-digestion, whereby intracellular disease has been posited (He et al., 2016), and consequently, proteins, fatty acids (FA), organelles, and cellular detritus the understanding of the molecular mechanisms underlying (cargo) are degraded by lysosomal enzymes and recycled into this relationship occurring in the liver may be the basis for their basic units, to be reused in the cytoplasm for survival, the design of new protective strategies for livers affected by differentiation, etc. (Mizushima et al., 2010; Miyamoto and metabolic diseases and undergoing a liver surgery process. The Heller, 2016). Autophagy can be selective or non-selective since vast majority of reviews that address the role of autophagy in this cellular response can be directed to degrade a specific obesity, MetS, insulin resistance, NAFLD or diabetes, does not organelle (i.e., mitophagy or lipophagy) (Kim et al., 2016). clearly distinguish which are the molecular signaling pathways Autophagy begins with the development and elongation of related to autophagy that come about at the liver tissue. a membrane, the phagophore that in turn, is transformed Therefore, the findings that have been reported about the effects into a vesicle surrounded by two membranes in which the of such metabolic diseases on the hepatic autophagy process are cargo is isolated. Microtubule-associated protein light-chain 3 presented below. (LC3) participates in the formation of autophagosomes; its cleavage by autophagy gen (Atg)4B results in LC3-I, which conjugates with phosphatidylethanolamine via two consecutive Metabolic Syndrome and Associated reactions catalyzed by the E1-like enzyme Atg7, and the E2- Disorders like enzyme Atg3, thus forming lipidated LC3-II associated with Although several studies have attempted to determine the origin the autophagosomal membrane. The autophagosome matures of the MetS, due to its complexity, a clear etiology remains to by fusing with lysosomes to create autophagolysosomes where be established. MetS refers to central obesity, insulin resistance, its selected cargo is degraded (Kabeya et al., 2000; Kirisako impaired glucose tolerance, dyslipidemia, and elevated blood et al., 2000). The p62/sequestosome (SQSTM) is a ubiquitin- pressure (Simmons et al., 2010). Excessive fat accumulation binding protein that recognizes ubiquitinated cargo and links in obesity associated with the MetS and its macrovascular with autophagosomes through direct interaction with LC3-II complications activates the immune system and chronic states (Lamark et al., 2003; Pankiv et al., 2007). Since LC3-II and p62 of low-grade inflammation. Altered signaling at the molecular are both degraded in the autolysosome with autophagic cargo, level in adipose tissue, negatively affects the liver as causes accumulation of LC3-II and p62 is regarded as a robust marker of hepatic infiltration by macrophages and other immune cells impaired autophagic flux (Lee et al., 2012). Lysosome-associated (Esser et al., 2014). This event is not the only one that damages membrane proteins (LAMPs) are essential for autophagosome- liver tissue. Once adipose tissue has reached its storage capacity, lysosome fusion during autophagy and are responsible for excess calories are redirected to other depots and lead to lysosomal proteolytic activity. When LAMP1 and LAMP2 are ectopic fat accumulation. Visceral fat drains into the portal inhibited, then autophagosome and lysosome fusion is inhibited, vein, and then the liver is targeted by multiple metabolites and this is associated with the accumulation of LC3-II and p62 and adipokines (Schleinitz et al., 2014). A connection between suggesting a decrease in autophagy flux (Fortunato et al., 2009). obesity, progressive lipid accumulation in the liver, and T2D Lysosomal proteases, such as cathepsin, also play a key role in humans has been established (Goto et al., 2017). Diabetes in autolysosome degradation (Uchiyama, 2001), and therefore, is linked particularly to NAFLD, and indeed, up to 70% of lysosome dysfunction may be involved with autophagic flux diabetic patients develop NAFLD (Williamson et al., 2011). impairment. In line with this, defective cathepsin B, cathepsin D, Hepatic lipids tend to further exacerbate insulin resistance by and cathepsin L enzyme activity resulted in impaired lysosomal interfering with insulin signaling, thus perpetuating the vicious acidification and this occurred concomitantly with autophagic cycle. In fact, FA increases gluconeogenesis, lipogenesis, and flux blockade, including autophagosome accumulation and chronic inflammation, which foster hepatic glucose production, decreased degradation of SQSTM1/p62 (Mareninova et al., resulting in hyperglycemia and hepatic insulin resistance (Pereira 2009). Considering all autophagy stages, there exists an updated et al., 2015; Wang Z. et al., 2017). consensus that suggests that the real status of autophagy should Based on evidence obtained from in vivo and in vitro studies, be assessed not only by the number of autophagosomes and autophagy has been suggested to underlie the pathophysiology autolysosomes but also by evaluating the actual autophagic of MetS, obesity, insulin resistance, and diabetes in the liver flux, such as monitoring the clearance of cell components in (Ogihara et al., 2002; Engeli et al., 2003; Yang et al., 2010; Putnam autolysosomes (du Toit et al., 2018). et al., 2012; Wang H.J. et al., 2015). Whether autophagy is a The liver is rich in lysosomes and has a high level of protective factor against obesity or a manifestation of impaired stress-induced autophagy. In fact, reactive oxygen species adipose tissue function, remains to be determined. Obesity is (ROS) give rise to lysosomal dysfunction and autophagy flux often associated with liver steatosis and insulin resistance. In impairment, avoiding the correct degradation of damaged obesity, autophagy decreases in hepatocytes, and metabolism is Frontiers in Cell and Developmental Biology | www.frontiersin.org 3 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome impaired. The release of lipids stored in droplets is mediated by the role and values of autophagic flux were not appropriately autophagy; if inhibited, promotes fatty liver development. Mice determined (the total process of autophagosome synthesis, with the hepatocyte-specific Atg7 deletion, develop fat droplets, substrate delivery, and lysosomal degradation) (Menikdiwela whereas Atg7 reestablishment ameliorates hepatic function. Yang et al., 2020). Thus, it is not possible to ascertain whether et al. described lower protein levels of Atg7, Beclin 1 (Atg6), such results are completely reliable as evidence of increased LC3, Atg5, and elevated p62 in the livers of obese mice (Yang autophagic activity. et al., 2010). Concerning other metabolic disorders, in rats with Several factors may regulate hepatic autophagy in MetS and MetS increased hepatic autophagy activity manifested by elevated related disorders. Hepatic ER stress suppresses autophagy in LC3-II/I, Beclin-1, mammalian target of rapamycin (mTOR), high-fat-fed mice and ob/ob mice, and disruption of autophagy and p62 autophagy-related proteins, as well as phosphorylated function by genetic ablation of Atg proteins can lead to ER adenosine 50 -monophosphate-activated protein kinase (AMPK) stress (Choi et al., 2018). Collectively, these data suggest that down-regulation, has been reported (Cui et al., 2020). These hepatic ER stress is directly related to the suppression of results appear to reflect an opposite role for autophagy in obesity autophagy. In genetic and in diet-induced mouse models of and MetS, however, they must be carefully analyzed. Since an obesity, lower levels of hepatic autophagy and increased ER increase in autophagy-dependent protein expression can result stress with concomitant insulin resistance, appear to follow a from one of two mechanisms, it could reflect either an increase pattern. Decreased autophagy led to greater ER stress and insulin in autophagosome synthesis or an arrest in degradation. resistance in murine hepatocytes (Menikdiwela et al., 2020). Accumulation of autophagosomes in the liver in the setting ER stress and increased lipogenesis are potential mechanisms of obesity has been demonstrated, and to explain this, a study accounting for insulin resistance mediated by high fructose carried out with a genetic obese experimental model found feedings. Higher levels of calpain 2 in hepatocytes decrease that a defect in lysosomal acidification and proteinase activity autophagy in obese models, while its inhibition increases of cathepsin impaired hepatic autophagic degradation (Inami it; melanocortin 3 receptor (MC3R) also regulates hepatic et al., 2011). On the other hand, an investigation performed autophagy by possibly acting on transcription factor EB (TFEB) with a diet-induced obese model indicated that impairment signaling. Another mechanism that decreases hepatic autophagy of autophagic flux was due to blockage of autophagosome- is via the forkhead box O (FOXO) transcriptional factor. FOXO is lysosome fusion, without alteration in lysosomal environment, a key regulator of vacuolar protein sorting 34 (Vps34) and Atg12, including acidification and hydrolytic function; and this was responsible for autophagy initiation. Its activity is suppressed by associated with ER stress (Miyagawa et al., 2016). These results increased insulin levels and serine-threonine protein kinase Akt would indicate that possibly, different experimental models could (Akt) activation, and hence, autophagy decreases in MetS (Liu induce variations in some autophagy signaling pathways. The et al., 2009). Nutrients and insulin also regulate the autophagy autophagosome-lysosome degradation process plays a role in the process in the liver, since they are two powerful suppressors pathogenesis of obesity-mediated diabetes. In mice, deficiencies of autophagy (Vanhorebeek et al., 2011). Regarding the effects in LAMP2, which is crucial in the fusion and degradation of of some nutrients, hepatic autophagy was suppressed in the autophagosomes with lysosomes, prevent the development of presence of ER stress after mice were fed high fructose diets high-fat diet (HFD)-induced obese T2D and increases energy for 2–12 h, 2 weeks, as well as in liver explants incubated with expenditure, in turn, associated with hepatic fibroblast growth fructose medium (Wang H. et al., 2015). Increased secretion factor 21 (FGF21) overproduction. The expression of ER stress- of insulin by β-cells decreases hepatic autophagy and promotes related proteins was increased in the liver of HFD-fed LAMP2- insulin resistance in hepatocytes (Quan et al., 2012). In line deficient mice and it was suggested that ER stress was involved with this, in MetS hyperinsulinemia up-regulates mammalian in the hepatic induction of FGF21 (Yasuda-Yamahara et al., target of rapamycin complex 1 (mTORC1) activity and suppresses 2015). In line with these results, it has been also reported hepatic autophagy. Concurrently, activated hepatic mTORC1 that insufficient autophagosome formation in the liver induced further phosphorylates the insulin receptor through ribosome mitochondrial stress, increased ATF4-FGF21 pathway activity, S6 protein kinase 1 (S6K1), and this leads to insulin resistance and protected from diet-induced obesity and insulin resistance (Wang et al., 2012). As regards hyperglycemia and diabetes, (Kim et al., 2013). hepatic autophagy comes to play an important role in glucose In the context of metabolic diseases, autophagy is a homeostasis (Wang H.J. et al., 2015). Cryptochrome 1 (CRY1) dynamic process in the liver that changes as a function of decreases hepatic glucose production, and its timely removal by time. Experimental studies demonstrate an increased hepatic autophagy promotes glucose production. Obesity increases CRY1 autophagy activity in HFD-induced obesity and hepatic steatosis. degradation by autophagy, thus increasing glucose production However, the raise of HFD-induced autophagy only lasts a few and circulating blood sugar levels (Toledo et al., 2018). weeks and in fact, it decreases in chronic obesity due to cellular Whether defective autophagy is cause or consequence of stress. In this sense, it has been observed that autophagy remains hepatic insulin resistance remains to be determined. This active for 7 weeks under HFD conditions, but disappears after distinction might be pivotal when managing diabetic patients the eighth week (Adkins et al., 2013). These results should undergoing liver surgery. For instance, if defective autophagy be cautiously interpreted. Although in several investigations induces insulin resistance, a promising strategy for such patients experimental results may indicate an increased expression of may be to treat hyperglycemia with short-term intensive insulin autophagy markers and autophagosome number, in such studies therapy, since autophagy is already defective, and this treatment Frontiers in Cell and Developmental Biology | www.frontiersin.org 4 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome has proven effective in the control of glucose levels (Kramer autophagosomal cargos for the maintenance of autophagic flux. et al., 2013). However, if an increase in insulin results in In NASH, the precursor form of cathepsin D, an enzyme cleaved decreased hepatic autophagy, insulin therapy may render the to its mature form upon acidification and involved in lysosome- liver vulnerable to other stressors. In diabetes conditions, dependent proteolysis, showed accumulation. In addition, the research indicates that there is an upregulation of autophagy and number of acidic lysosomes was reduced in steatotic hepatocytes. therefore, a decrease in autophagy could be useful in hepatic These events could be associated with the increased synthesis glucose homeostasis regulation, and to a certain extent, prevent of asparagine by asparagine synthetase (ASNS). Expression of the development of diabetes and its complications. Although ASNS was elevated in steatohepatitis and knockdown of ASNS these findings contribute to a better understanding of the role restored autophagic flux in MCD medium–cultured hepatocyte of autophagy in the liver affected by diabetes, there is still cell lines, as evidenced by the decreased accumulation of p62. very little literature on the molecular events underlying hepatic As well, asparagine exposure in hepatocytes directly inhibited autophagy in diabetic conditions, indicating that more research lysosome acidification, as evidenced by the failed cleavage of is required in this regard. procathepsin D to its mature form, and the reduced number of acidic autolysosomes (Wang et al., 2018). In addition, to NAFLD defects in acidification of lysosomes, other causes of lysosomal Non-alcoholic fatty liver disease is the most common cause dysfunction related to worsened autophagic flux have been of abnormal liver function and it covers a broad spectrum of described in NAFLD-NASH. Chemokine (C-X-C motif) receptor liver changes, ranging from simple steatosis to non-alcoholic 3 (CXCR3) inhibited autophagic flux in steatohepatitis since steatohepatitis (NASH), liver cirrhosis, and hepatocellular ablation of CXCR3 reduced p62 and LC3-II accumulation and carcinoma (Zhang et al., 2018). The prevalence of NAFLD is ameliorated steatohepatitis. In this context, CXCR3 induced on the rise throughout the Western world since it is strongly LAMP1 and LAMP2, which are membrane proteins crucial associated with obesity, insulin resistance, MetS, and T2D. In fact, in autophagosome-lysosome fusion and proteolytic activity, NAFLD is generally considered to be the hepatic manifestation of indicating lysosome storage disorder (Zhang et al., 2016). MetS, and research has confirmed that hepatic lipid accumulation According to what happens in other diseases, upregulation is responsible for hepatic insulin resistance and whole-body of LAMP might suggest an increase in the overall lysosomal insulin resistance. Lee et al. have reported that obese adolescents mass that could be interpreted as an attempt to counteract with fatty liver are at greater risk of developing systemic insulin lysosomal dysfunction (Houben et al., 2017). Last but not least, resistance than those with a healthy liver (Lee et al., 2015). an increment in intracellular lipids, as occurs in NAFLD-NASH, Thus, NAFLD has become a major public health issue, with altered the intracellular membrane lipid composition of both potentially serious consequences (Parafati et al., 2015). In this autophagosomes and lysosomes. This reduced the ability of sense, NAFLD is rapidly becoming the leading indication for liver autophagosomes to fuse with lysosomes and led to a decrease in transplantation (Zhang et al., 2018). autophagic flux (Koga et al., 2010). A consensus has been reached, suggesting that autophagy Hepatic ER stress and autophagy dysfunction increase plays a crucial role in the pathogenesis of NAFLD, and in with the onset of NAFLD in patients and dietary-induced fact, several studies have indicated impaired autophagy (Samala obese models, whereas suppressing ER stress and activating et al., 2017). Autophagy is inhibited in the livers of NAFLD and autophagy ameliorate high-fat-induced hepatocyte apoptosis NASH murine models. Furthermore, enhancing autophagy by (Wang H. et al., 2015). NAFLD development requires additional overexpressing Atg7, improved hepatic steatosis in ob/ob mice diverse signaling pathways and mediators. In steatotic livers, and mice fed a HFD (Gong et al., 2016). Increased levels of LC3- autophagy is mainly regulated by the AMPK-mTOR and silencing II and p62 reflect a defect in the autophagic flux (a failure in the information regulator 1 (Sirt1)-FOXO pathways, which are clearance of autophagosomes), and this has been observed in the activated by increased adenosine diphosphate (ADP)/adenosine liver of C57BL/6 mice when fed a HFD. Similar results have been triphosphate (ATP) ratios and nicotinamide adenine dinucleotide reported in mice fed a methionine/choline-deficient (MCD) diet (NAD +), respectively (Figure 1). Several studies suggest that is usually used to induce NASH (Wang et al., 2018). Also, that AMPK activation or Sirt1 induction restore impaired autophagy markers, LC3-II and p62, were impaired in the liver of autophagy and ameliorate hepatic lipid accumulation (Huang genetically leptin-deficient ob/ob mice that are obese and insulin et al., 2017). The TFEB is another autophagy regulator that resistant, and that develop NAFLD like that observed in humans positively modulates lipid catabolism, as a result of the (Yang et al., 2010). The presented body of evidence suggests direct induction of the “coordinated lysosomal expression and that under these conditions, clearance of autophagosomes is regulation” (CLEAR) network, which includes genes that control impaired. In NAFLD and NASH patients, p62 and LC3-II levels autophagy, lysosome biogenesis, and lipolysis (Wang Z. et al., are increased and reflect autophagic flux impairment in the 2017). Interestingly, TFEB overexpression in mice in which diseased livers (González-Rodríguez et al., 2014). Regardless, autophagy was genetically suppressed by deletion of hepatic normal p62 values have also been reported in NAFLD and Atg7, did not preclude the development of or decrease fatty NASH patient livers (Lee et al., 2017). This issue remains a infiltration in hepatic steatosis, suggesting that the effects of TFEB controversial subject. In the context of these metabolic diseases, on lipid metabolism require a functional autophagic pathway a deficient autophagic flux is related to lysosome dysfunction. (Settembre et al., 2013). The induction of autophagy is dependent Autolysosome acidification is critical to the degradation of upon nutrient conditions, whereby in nutrient-rich conditions, Frontiers in Cell and Developmental Biology | www.frontiersin.org 5 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome FIGURE 1 | Autophagy signaling pathway in steatotic liver. Atg7, Beclin1, LC3-II, and p62 has been described as markers of autophagy in fatty liver, and this process is regulated by AMPK-mTOR, Sirt1-FOXO, and TFEB. In this type of liver, autophagy is interrelated with UPS, ER stress, JNK, ghrelin, and NLRP3 inflammasome signaling pathways, among others. As a result of interaction between all these mediators, dysfunction in lipid accumulation and inflammation may occurs in steatotic liver. Some diet components such as excess fat, palmitate, oleate or fructose could alter hepatic autophagy in steatotic livers and therefore affect NAFLD progression. mTOR inhibits the initiation of autophagy. Perhaps as a result is observed in the liver of mice fed a HFD (Samala et al., 2017). of over-nutrition, mTOR signaling is frequently hyperactivated Palmitate (one of the most abundant FA in the plasma of humans in the livers of obese mice and also suppresses TFEB activity and rodents) is poorly converted into triglyceride-enriched lipid (Singh et al., 2009). Hepatic steatosis improved in HFD-induced droplets (LD), and inhibits autophagy by inducing the caspase- NAFLD, after mTOR inhibitor treatment, rapamycin (Gong dependent cleavage of Beclin1; its presence also induces a degree et al., 2016). Autophagy is also dependent on c-Jun NH(2)- of lipid-induced apoptosis (lipoapoptosis) in hepatocytes (Ricchi terminal kinase (JNK) whereby JNK activation contributes to et al., 2009). On the other hand, monounsaturated FA, such as Beclin-1 expression and modulates autophagy. Inhibition of oleate, stimulate the formation of triglyceride-enriched LD and JNK suppresses autophagy and decreases insulin resistance in induce autophagy but hardly affects lipoapoptosis. The formation NAFLD (Yan et al., 2017). Different ghrelin isoforms might of LD and the induction of autophagy are known to be protective upregulate autophagy and ameliorate liver disease, as proven in mechanisms against saturated FA-induced lipotoxicity (Mei et al., preclinical and clinical studies. It appears that acyl ghrelin up- 2011). These data indicate that not only excessive nutrition per se regulation stimulates hepatic autophagy by suppressing tumor but also diet composition, are crucial factors fomenting NAFLD. necrosis factor alpha (TNF-α) production via AMPK/mTOR. Long-lasting intake of certain nutrients can also modulate hepatic This protective mechanism leads to NAFLD improvement autophagy. After 4 weeks of consuming a HFD, autophagy (Chorny et al., 2008). However, in experimental acute hepatitis was activated to protect hepatocytes from lipotoxicity; further, and liver fibrosis, ghrelin administration decreases hepatic apoptosis was activated after a HFD intake for 8 weeks, and autophagy (Mao et al., 2015). These different ghrelin effects may autophagy initiation was suppressed. After 16 weeks on the HFD, result from differences in experimental conditions, drug doses, an increase in the LC3II/LC3I ratio was demonstrated, suggesting and cellular physiological states. that functional autophagy was disrupted after HFD consumption Dietary nutrients could affect autophagy in the liver and lasting more than 8 weeks (Hsu et al., 2016). A high fructose consequently regulate NAFLD progression. Under starvation, diet also suppresses liver autophagy and appears to be mediated active autophagy leads to lipolysis and free FA production, by the activation of mTOR. High fructose-induced suppression providing additional energy sources. In conditions of excessive fat of autophagy may cause ER stress, and the resulting changes accumulation in the liver, autophagy is downregulated, leading in JNK/inhibitor of NF-κB kinase (IKK) and insulin signaling to an additional increase in lipid accumulation in the liver, as it cascades. When autophagy is restored with pharmacological Frontiers in Cell and Developmental Biology | www.frontiersin.org 6 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome agents, ER stress is improved and all associated injurious events decreased, and also autophagy impairment is attenuated, thus caused by a high fructose diet are corrected (Wang H. et al., 2015). indicating that Rubicon could abolish lipophagy, and hence cause the deposit of LD in the liver (Tanaka et al., 2016). Lipophagy, a Form of Selective Autophagy, Is Enhancing lipophagy clears hepatocellular LD and this could Significant in NAFLD drive to a strategy to mobilize hepatic lipids and prevent human Lipophagy selectively degrades LD which are incorporated in NAFLD. An important issue to ponder is the possible cooperation vesicles, transported to lysosomes, and finally degraded into or synergy between lipolysis and lipophagy in the regulation FA. This lipid degradation pathway in hepatocytes explains of hepatic lipid metabolism. Lipophagy may degrade larger LD their ability to rapidly mobilize large amounts of lipids despite into smaller droplets, which in turn increases LD surface area low levels of cytosolic lipases when compared with adipocytes upon which cytosolic lipases can exert their action (Zhang (Zhang et al., 2018). In fact, sustained abnormalities in lipophagy et al., 2018). Recognizing lipophagy as an elementary process in hepatocytes might be the basis of liver steatosis and regulating lipid clearance in the liver enlightens new possibilities steatohepatitis (Schott et al., 2019). Continuing studies in humans to design therapies that promote hepatic lipophagy and improve or animals have established that lipophagy contributes to the metabolic diseases. NAFLD development (Schulze and McNiven, 2014; Xiong et al., 2016; Chen et al., 2017b). As blood lipids infiltrate the liver, Mitophagy and NAFLD upregulation of the biogenesis of LD acts as a defense mechanism Mitochondrial autophagy (mitophagy) is a mitochondrial against toxic FA that are esterified into triglycerides and stored in quality control process that degrades damaged mitochondrion LD. Pharmacological or genetic inhibition of autophagy increases and suppresses their production of ROS that might lead triglyceride and cholesterol contents, and LD number and size, in to mitochondrial dysfunction (Adeva-Andany et al., 2019). hepatocytes treated with free FA and in mice fed a HFD. On the Hepatic FA accumulation can cause damaged mitochondria opposite, enhancing autophagy by Atg7 overexpression improved accumulation, which in turn, hinders mitochondrial respiratory hepatic steatosis and insulin resistance in ob/ob mice and mice chain function, and FA oxidative degradation. The accumulation fed a HFD (Jeong Kim et al., 2017). Thus, this emerging evidence of dysfunctional mitochondria leads to BCL2 and adenovirus points that lipophagy could be a therapeutic target in NAFLD. E1B 19-kDa-interacting protein 3 (BNIP3)/BNIP3-like (BNIP3L, In the liver, lipophagy is mediated by complex transcriptional also known as NIX) (NIX)-mediated mitophagy, clearance of regulators of autophagy genes and is inhibited by the insulin mitochondrial debris, and the reestablishment of mitochondrial and amino acid-mTOR signaling pathway via short- and long- function. Phosphatase and tensin homolog (PTEN)-induced term regulation mechanisms. Short-term inhibition is dependent putative kinase 1 (PINK1)/Parkin is another molecular on the mTOR complex, while long-term regulation is mediated mechanism that could be involved in hepatic mitophagy by the transcription factors FOXO and TFEB (Stayrook et al., (Sato and Furuya, 2017). 2005; Oberkofler et al., 2010). Insulin receptor activation Studies on mitophagy in NAFLD and related metabolic induces de novo lipogenesis and prevents autophagy-mediated comorbidities are still scarce, however, they show that this LD degradation (Bechmann et al., 2012). Other regulators of molecular pathway could have broad therapeutic possibilities. lipophagy in the liver have been described. Oxidative stress Impaired mitophagy promotes macrophage infiltration that appears to affect lipophagy, in fact, LD accumulated more activates mitogen-activated protein kinase (MAPK) pathway, readily in the liver in SOD1-knockout mice compared with and causes inflammation, impairing mitochondrial quality the wild-type mouse, under fasting conditions. Lipophagy control, and fostering the development of insulin resistance was abolished by oxidative stress, and lipoprotein secretion and hepatic steatosis. It has been demonstrated that stimulating was suppressed in superoxide dismutase (SOD)1 deficiency, mitophagy can inhibit hepatic lipid accumulation and temper ultimately leading to LD accumulation (Kurahashi et al., insulin resistance (Su et al., 2019). In an experimental model of 2015). Further, ROS increases perilipin 2 (PLIN2), which NAFLD, abnormal PINK1/Parkin-dependent mitophagy might induces LD accumulation by blocking autophagy and negatively be responsible for hepatic FA accumulation and treatments affecting droplet breakdown (Jin et al., 2018). Therefore, hepatic aimed at increasing PINK1/Parkin-mediated mitophagy autophagy induction might modulate LD accumulation and ROS (as quercetin), accelerated mitochondrial FA oxidation, generation. Immunity-related guanosine triphosphatase family and suppressed FA accumulation. Quercetin also activated M (IRGM) is another key gene involved in lipophagy regulation, PINK1/Parkin-dependent mitophagy and prevented oleic as IRGM knockdown inhibited autophagy and increased LD acid/palmitic acid-induced lipid accumulation in HepG2 cells content in HepG2 and PLC/PRF/5 cells, and this process (Liu et al., 2018). Linseed oil, exenatide, melatonin, akebia could be reversed by rapamycin (Lin et al., 2016). FGF21 saponin D, and sirtuin 3 have also evidenced to reduce hepatic can ameliorate NAFLD, partly re-establish insulin sensitivity, lipid accumulation by enhancing mitophagy (Gong et al., 2018; and correct several metabolic parameters through lipophagy Li R. et al., 2018; Shao et al., 2018; Zhou et al., 2018; Yu et al., in HepG2 cells overloaded with lipids (Zhu S. et al., 2016). 2019). On the other hand, it also has been described that in The run domain beclin-1-interacting and cysteine-rich domain- advanced NAFLD, mitophagy increases, and mitochondrial containing protein (Rubicon) inhibit late-stage autophagy during mass, mtDNA, and PGC-1α expression are reduced; this the autophagosome-lysosome fusion. In livers with impaired combines with compromised ATP production, resulting in a Rubicon expression, ER stress and the accumulation of LD vicious cycle of mitochondrial depletion and liver dysfunction. Frontiers in Cell and Developmental Biology | www.frontiersin.org 7 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome This later finding could mean that pharmacological interference therapeutic strategies for livers affected by metabolic diseases and with mitophagy molecular mechanisms may lead to therapeutic undergoing surgery. approaches (Lee et al., 2018). As can be seen, there are still serious There are many studies regarding the role of autophagy in controversies about the role of mitophagy in NAFLD that must NAFLD without surgery. In them decreased liver autophagy be resolved in order to design efficient strategies in the treatment seems to be a common finding in various experimental models of metabolic liver diseases. of NAFLD. However, it remains to be clarified whether the reduction in autophagy is the cellular event that results in hepatic steatosis or occurs after the liver has accumulated a significant Future Directions From the Role of amount of lipids. It is also unknown whether autophagy changes Hepatic Autophagy in Metabolic Liver in the function of different degrees of steatosis. Additionally, Diseases although several molecular mechanisms related to autophagy Currently, existing knowledge about the autophagic response have been described in the steatotic liver, there are controversies in the liver when obesity, MetS, insulin resistance, NAFLD, or about which ones precede autophagy failure and which ones are diabetes are present, does not allow one to establish if a defect a consequence of such dysfunction. in the capacity of the liver to induce autophagy is the underlying Regarding the selective forms of autophagy (lipophagy and cause for the appearance of such metabolic diseases. Regulation mitophagy) in livers affected by metabolic diseases, more research of hepatic autophagy seems to change throughout a metabolic is mandatory. In the case of NAFLD, very few underlying disease, since while in the first weeks of obesity there is an molecular mechanisms for lipophagy and mitophagy have been increase in autophagy markers, after a few months autophagy described, whereby more research is needed in this regard, decreases considerably (Adkins et al., 2013). In addition, although being of special interest those mediators that could be directly most studies suggest that a defect in liver autophagy invariably or indirectly related to inflammation, damage, or cell death accompanies obesity, MetS, insulin resistance, and NAFLD, some in the liver. Moreover, given the central role of mitochondrial reports indicate that autophagy could be overactive in diabetes quality control on lipid degradation and suppression of hepatic (Yasuda-Yamahara et al., 2015; Choi et al., 2018; Menikdiwela lipid accumulation, the active search, and understanding of the et al., 2020). The need to investigate in more detail the role of signaling pathways involved in lipophagy and mitophagy in autophagy in livers affected by obesity, MetS, insulin resistance, metabolic liver diseases, could yield new therapeutic options in NAFLD, and/or diabetes is evident since this step is crucial for the prevention and treatment of insulin resistance, MetS, NAFLD the design of new therapies that can improve the postoperative or diabetes in patients requiring liver surgery. results of this type of livers when they undergo surgery and are susceptible to being damaged by I/R injury. To achieve this, first, it is important to characterize whether one or more metabolic comorbidities are present in experimental models EFFECTS OF METABOLIC SYNDROME used at present, seeing that many studies use HFD models AND RELATED DISEASES ON LIVER to induce and study obesity but do not include results that SURGERY allow knowing if animal model also exhibits MetS or insulin resistance (Gracia-Sancho et al., 2013; Zaouali et al., 2017; Non-alcoholic fatty liver disease is the MetS-associated disease Panisello-Roselló et al., 2018). On the other hand, although whose effects in liver surgery have been studied the most. there have been multiple versions of consensus within the Numerous studies have established the enormously damaging autophagy community on the use and interpretation of assays role of hepatic steatosis in I/R injury in both liver resection for monitoring autophagy (Klionsky et al., 2021), it is notorious and transplantation. Surgical removal remains the only therapy that incompliance of investigations to the established guidelines for liver tumors with an elevated risk of failure in steatotic led to a discrepancy in experimental results in hepatic autophagy livers. To avoid blood loss during liver resection, portal inflow in the setting of metabolic diseases. For example, while various is temporarily occluded, leading to a warm ischemic period that publications indicate hepatic autophagy enhancement based may provoke relevant liver damage upon reperfusion. Steatosis on results showing high levels of LC3II or Beclin-1, other not only accentuates the liver’s susceptibility toward ischemic investigations interpret that the reduction in levels of these insults but also hinders its regenerative capacity in terms of parameters means an increase in autophagic activity (Parafati both repairing ischemic injury and counteracting for lost volume et al., 2015; Gong et al., 2016; Shao et al., 2018; Cui et al., following resection. Together, these characteristics lead to an 2020). Therefore, to explain controversies of existing results on increased frequency of postoperative complications that restrain hepatic autophagy in obesity, MetS, insulin resistance, NAFLD, surgical possibilities in patients with fatty liver (Linecker et al., or diabetes, it is necessary to adhere to the existing consensus 2017). In addition, NAFLD makes liver grafts too sensitive to cold on autophagy parameters, which would permit to have the most I/R inherent with transplantation, and thus, steatosis is correlated appropriate autophagy mediators in the liver to indicate with with a greater risk of graft malfunctioning, and consequently greater certainty an increase in the formation of autophagosomes higher postoperative morbidity and mortality in the recipient. and if lysosomal degradation is being carried out properly. Once Because of so high a percentage of people with NAFLD, many the role of hepatic autophagy in these pathological conditions potential donors are not eligible for donations (Forbes and is more precisely understood, it will be possible to design Newsome, 2016). Due to the present epidemic of obesity, the Frontiers in Cell and Developmental Biology | www.frontiersin.org 8 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome repercussion of hepatic steatosis in the setting of liver surgery is enhancement of peroxisome proliferator-activated receptor expected to continue to rise (Tashiro et al., 2014). gamma (PPAR-γ) (Casillas-Ramírez et al., 2008). Interestingly, Considering that steatotic livers tolerate I/R poorly, there is in liver transplantation, angiotensin II did not play a role growing comprehension of molecular and cellular mechanisms in cold I/R in steatotic grafts, and therefore, treatment with underpinning the development of I/R injury in patients with angiotensin II receptor antagonists was useless in this type of fatty livers. These molecular mechanisms of damage are very grafts (Alfany-Fernandez et al., 2009). ER stress has shown to different from those occurring in healthy livers (not affected by be a useful therapeutic target to reduce ischemic damage in NAFLD) subjected to I/R. In this way, hepatocyte damage is steatotic livers submitted to resection under vascular occlusion markedly higher in steatotic livers than in non-steatotic ones and (Ben Mosbah et al., 2010) but this did not happen in steatotic contributes to their poor tolerance to I/R (Selzner et al., 2000). liver transplantation (Jiménez-Castro et al., 2012). Cortisol levels Hepatocyte de-regulation has several causes, such as elevated in the liver were elevated in steatotic livers undergoing resections susceptibility to ROS that affects mitochondrial processes and (hepatectomy and warm I/R) and such elevations were attributed subsequently, ATP synthesis (Caraceni et al., 2005). Moreover, to a raise in cortisol production, and a decrease in cortisol hepatocytes with fatty infiltration develop massive necrosis after clearance. Cortisol administration exacerbated tissue damage I/R injury, rather than apoptosis observed in non-steatotic and regenerative failure, and such injurious effects were linked livers (Fernández et al., 2004). This fact might explicate why to high hepatic acetylcholine levels (Cornide-Petronio et al., caspase inhibition, a protective strategy in non-steatotic livers, 2017). Interestingly, although steatotic liver grafts also exhibited has no effects on hepatocyte injury in steatotic livers (Selzner increased cortisol after transplantation due to the same causes et al., 2000). In experimental models of liver transplantation, that in hepatic resection (augment in cortisol generation and exogenous nitric oxide (NO) administration reduce damage diminishment in cortisol clearance), in liver transplantation in non-steatotic grafts but is useless, or even harmful, in exogenous administration of cortisol treatment up-regulated the steatotic livers. The deleterious effects of exogenous NO are PI3K-protein kinase C (PKC) pathway, resulting in protection explained by exaggerated peroxynitrite generation caused by against the deleterious effects of brain death on damage ROS overproduction (Carrasco-Chaumel et al., 2005). Steatotic and inflammatory response in steatotic liver transplantation livers also diverge from non-steatotic grafts in their response to (Jiménez-Castro et al., 2017). All these experimental results the unfolded protein response (UPR) and ER stress, indeed the highlight a different role for several mediators in the regulation of expression of inositol-requiring enzyme 1 (IRE1) and protein damage in steatotic livers, depending on the type of surgery. This kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is indicates that finding feasible and highly protective therapeutical lower in the presence of steatosis (Ben Mosbah et al., 2010). strategies to reduce the adverse effects of NAFLD on liver surgery A very important aspect that must be contemplated, is that entails exhaustive evaluation of potential therapeutic targets and although in both, resection and transplantation, steatosis worsens strategies based on its modulation in appropriated experimental postoperative outcomes, the signaling pathways underlying models for each surgical setting. hepatic injury are substantially different in each surgical setting, The effects of obesity, insulin resistance, and MetS in liver this means, depending on warm or cold I/R occurs. Indeed, in surgery have not been separately investigated. There are some each type of surgery there exist distinct therapeutic targets and studies that, considering the experimental model used, one could therefore, treatments that work in one surgical situation might assume that various metabolic diseases are present, such as not function in the other. In accordance, increased adiponectin NAFLD in combination with MetS, obesity, or insulin resistance; levels were observed in steatotic livers as a consequence of but unfortunately, they report confusing information about the warm I/R associated with hepatic resection, and then, the precise diagnosis of such comorbidities. A great milestone for treatment with adiponectin small interfering ribonucleic acid future research on I/R in the liver with metabolic comorbidities (RNA) protected steatotic livers against oxidative stress and in appropriated experimental models would be to include hepatic injury (Massip-Salcedo et al., 2008). On the opposite, parameters that facilitate the establishment of the presence of when subjected to transplantation, steatotic liver grafts exhibited concurrent metabolic diseases and the effects of the tested downregulation of adiponectin. Adiponectin pre-treatment treatments on them. protected steatotic grafts activating the phosphoinositide-3 There are a few studies about the effects of hyperglycemia kinase (PI3K)/Akt pathway and unraveling AMPK as an or diabetes in liver surgery. Hyperglycemia has been shown to upstream mediator of adiponectin’s actions in steatotic grafts worsen hepatic warm I/R injury by inducing hyperinflammatory (Jiménez-Castro et al., 2013). Similarly, a therapy based on immune responses through activation of advanced glycation modulating retinol binding protein 4 (RBP4) has proven to end product (AGE)-receptor for AGE (RAGE) pathway in impair damage and liver regeneration in steatotic livers in Kupffer cells (Wang Q. et al., 2020). Several factors may explain the setting of hepatectomy under warm I/R; whereas the the mechanisms underlying the pathological and functional same therapeutical strategy was beneficial in steatotic livers changes in liver injury-induced hyperglycemia, including insulin undergoing transplantation (Casillas-Ramírez et al., 2011; Elias- resistance, inflammation, and oxidative stress. Diabetic animals Miró et al., 2012). In addition, warm I/R produced an increase in show the decreased hepatic activity of antioxidant enzymes such angiotensin II which injured steatotic livers, and pharmacologic as catalase and SOD, thus increasing ROS, which can damage blockers of angiotensin II action, such as angiotensin II receptor lipids, proteins, desoxyribonucleic acid (DNA), compromise antagonists, protected steatotic livers against I/R injury through mitochondria or ER function, thus leading to cell homeostasis Frontiers in Cell and Developmental Biology | www.frontiersin.org 9 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome failure and cell death. Considering that T2D is associated with use of insulin. Recurrence should be further evaluated in larger hepatic lipid accumulation and that lipids are highly susceptible studies, with special emphasis on the management of MetS to being damaged by ROS, oxidative stress represents a major and prevention strategies (El Atrache et al., 2012). Curtailing issue in liver function in these patients (Gjorgjieva et al., the development of postoperative MetS after orthotopic liver 2019). Pro-inflammatory mediators involved in hyperglycemic transplantation, may decrease readmissions and improve patient liver injury include interleukin (IL)-1 and IL-6, nuclear factor and graft outcomes (Chang et al., 2016). kappa B (NF-kB), MAPK, transforming growth factor (TGF), poly (ADP-ribose) polymerase (PARP), and TNF-α. Indeed, diabetic rat models have confirmed that in the liver, the AUTOPHAGY IN LIVER SURGERY IN THE induction of TNF-α results in increased NF-kB and JNK SETTING OF METABOLIC SYNDROME signaling, nitric oxide production, and apoptosis (Manna et al., 2010; Ingaramo et al., 2011). All these mediators and events The majority of research about autophagy in liver surgery has occurring during oxidative stress and inflammation are part of been focused on healthy livers more than on livers affected by the underlying signaling mechanisms in I/R, so when surgery MetS or related metabolic diseases. Such investigations have occurs in the presence of hyperglycemia, the production of allowed us to distinguish the relevance of autophagy in liver these mediators would be exacerbated and result in major liver surgery outcomes and a better mechanistic understanding of the injury. Inflammation and oxidative stress can negatively affect autophagy process in resection and transplantation, which makes insulin sensitivity. In fact, ROS can inhibit insulin signaling it possible to conceive new therapeutic options that could be by inducing Insulin Receptor Substrate (IRS) degradation in evaluated in livers suffering metabolic diseases and submitted peripheral tissues, a cause of insulin desensitization (Archuleta to surgery. In some cases, findings on autophagy in I/R injury et al., 2009). TNF-α has also been shown to induce insulin in healthy livers have been reflected in the clinical setting. This resistance (Alipourfard et al., 2019). supports that results in autophagy in liver surgery in the setting The negative effects of metabolic diseases in liver surgery of metabolic diseases might be translated from the laboratory have been described at the clinical level, and it has been shown toward a possible new clinical therapy. Therefore, this section that they can also affect a patient’s condition in the medium or first discusses the existing knowledge on the role of autophagy long term after surgery. Transoperative stress hyperglycemia is in liver surgery without the effect of MetS or related diseases; a common clinical finding due to a transient decrease in insulin subsequently, published results regarding the role of autophagy responsiveness that may persist from days to weeks after major in I/R in livers with MetS and associated diseases are analyzed; surgery. Patients without established diabetes mellitus and who and finally, new lines of research that could be approached in develop stress hyperglycemia, are at higher risk of poor outcomes, the future to improve the results of liver surgery in the setting depending on the severity and duration of stress hyperglycemia of metabolic diseases are discussed. (Chae et al., 2020). For example, hemi-hepatectomy results in moderate disturbances in glucose homeostasis that are of Autophagy in Hepatic I/R Injury no clinical relevance. However, early exacerbation of insulin The pathogenic signaling pathways in hepatic I/R have been resistance results in a greater risk of developing overt diabetes documented to be different in normothermic vs. cold ischemia, in the long term (Durczynski et al., 2013). Along the same and even in livers in optimal conditions and those with lines, diabetes negatively impacts the surgical outcome of patients underlying pathological conditions such as steatosis. Then, it is with cirrhosis after liver resection and transplantation, and the foreseeable that the autophagy process also works differently in stress associated with the post-reperfusion syndrome further I/R injury in livers depending on whether they undergo resection increases hyperglycemia and insulin resistance during surgery or transplantation. The design of therapeutic strategies based in recipients with reduced-size liver grafts (Chae et al., 2020). on autophagy modulation to protect livers suffering metabolic Although the exact mechanisms responsible for these adverse disorders and subjected to surgery, largely depends on a clear outcomes are not completely elucidated, a probable cause understanding of the molecular mechanisms of autophagy in seems to be the increase in I/R injury resulting from the liver I/R injury, distinguishing between liver resection and acute hyperglycemic disturbances. As a result, the early post- transplantation models. reperfusion period is critical since significant hepatic insults are inflicted, and graft regeneration is concurrently initiated Autophagy in Warm I/R Injury Associated With with metabolic and detoxifying associated phenomena (Kang Hepatic Resection et al., 2018). Moreover, liver transplantation recipients have Many reports in the literature strongly support a relevant role been shown to progressively develop MetS in a high proportion of autophagy in I/R injury in liver resection. Recent research despite current efforts to mitigate their evolution (i.e., lifestyle on this topic has focused on the discovery of novel molecular modifications and aggressive management of hypertension, signaling mechanisms that, in the first instance, are being diabetes, and hyperlipidemia). Associated risk factors include age, studied in experimental models with optimal livers (without increased body mass index, and pre- and post-transplantation steatosis or other metabolic comorbidities). Table 1 summarizes serum glucose (Vida Perez et al., 2016). Importantly, increased the studies in the literature on autophagy in warm I/R that recurrence of NASH and cryptogenic cirrhosis was associated have been conducted in the last 5 years. As shown, results with the presence of concomitant MetS, hypertension, and the have been contradictory, since some indicate that increased Frontiers in Cell and Developmental Biology | www.frontiersin.org 10 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome autophagy protects livers subjected to I/R, while others report studies using allogeneic optimal liver grafts (Lewis rat donor that it is the inhibition of autophagic activity that leads to and Norway rat recipient), there are disagreements. In a study beneficial effects. These findings are most likely due to the based on transplantation with a small-size liver graft, a discrete different experimental models used, including the different increase in some autophagy parameters was detected, and the durations of ischemia and/or reperfusion. It is widely known that grafts were protected by increasing autophagic activity through experimental conditions influence the mechanisms underlying cell therapy combined with gene overexpression; this led to a liver I/R, and hence, the results. decrease in the rejection rate. In another study, benefits for graft Some findings in signaling molecular pathways lately viability (reduction of injury and graft rejection) were obtained described in warm ischemia are included following. Long-non- by administering drugs to inhibit autophagy (Wang R. R. et al., coding RNAs (lncRNAs) homeobox (HOX) transcript antisense 2017; Chen et al., 2019b). In these cases, the main difference RNA (HOTAIR), regulated autophagy via the microRNA that could explain the contradictory results was the decrease in (miR)-20b-5p/ATG7 axis in I/R injury in mice subjected to the liver graft size in one of the models. Small grafts are known partial hepatic ischemia (Tang et al., 2019). HOTAIR and to exhibit a much greater hepatic regeneration response than ATG7 expression levels increased as did autophagy during I/R whole-size grafts (González et al., 2010). Perhaps, mechanisms injury, while the knockdown of HOTAIR expression attenuated underlying regeneration may influence other signaling pathways autophagy in isolated hepatocytes (Tang et al., 2019). During including autophagy; therefore, autophagy modulation in small- experimental hepatic I/R injury, the master transcription factor size transplants might induce different effects on liver injury than Interferon Regulatory Factor (IRF1) was upregulated and in whole-size transplants. associated with activation of autophagic signaling (Yu et al., Investigations about the role of autophagy in clinical liver 2017). IRF1 also inhibited β-catenin expression in livers subjected transplantation are very limited. Research conducted to date, to I/R injury, it activated autophagy and worsened hepatic injury indicates that in optimal and steatotic transplantation, there (Yan et al., 2020). MicroRNA refers to a highly conserved, small, is usually a slight expression of autophagy markers (Degli non-coded RNA, associated with basic cellular processes, such Esposti et al., 2011; Ricca et al., 2015; Nakamura et al., 2018, as apoptosis, proliferation, and stress responses. MicroRNAs 2019; Chen et al., 2019b). It is important to note that in have been shown to also play a role in autophagy regulation. steatotic grafts, published reports do not specify whether the In vivo and in vitro miR-30b levels are down-regulated after donors presented any metabolic comorbidity such as insulin hepatic I/R injury, and simultaneously, activate autophagy. High resistance or the MetS. Although no strategy to directly levels of miR-17 upregulate autophagy and worsen hepatic I/R regulate autophagy has been applied yet in clinical practice, injury by suppressing Stat3 expression in vitro (Li et al., 2016). results suggest that steatotic and non-steatotic transplanted liver Interestingly, mitophagy is involved in warm hepatic ischemia, grafts may benefit from strategies promoting autophagy, such and some molecular mediators related to this process are the as ischemic postconditioning, ischemic preconditioning, and following: (a) Parkin expression and mitochondrial autophagy recipient treatment with antibiotics to modulate gut microbiota are up-regulated after I/R injury (Ning et al., 2018); (b) PINK1 (Degli Esposti et al., 2011; Ricca et al., 2015). This indicates (a mediator of mitophagy) protected against hepatic I/R injury that the mechanisms underlying I/R injury and associated with by preventing nucleotide-binding oligomerization domain autophagy that have been described at the experimental level, also (NOD)-like receptor (NLR) family pyrin domain containing 3 seem to occur at the clinical level. It encourages the study of new (NLRP3) inflammasome activation in mice subjected to partial experimental strategies that are capable of modulating autophagy warm I/R (Xu et al., 2020), and (c) miR-330-3p suppresses to improve postsurgical outcomes in steatotic liver grafts that are phosphoglycerate mutase family member 5 (PGAM5)-induced also compromised by metabolic comorbidities, and that later can mitophagy to dampen hepatic I/R injury (Sun et al., 2019). be translated to clinical practice. Autophagy in Cold I/R Injury Inherent to Liver Transplantation Autophagy in Livers Affected by Table 2 summarizes the studies evaluating the role of autophagy Metabolic Diseases and Undergoing in liver transplantation. In optimal liver transplantation models Surgery subjected to various cold storage times, a slight increase or To date, there are only studies on autophagy involvement in liver no change in autophagy parameters are usually observed as surgery in the setting of NAFLD or hyperglycemia. However, a result of ischemic insult. The various strategies that have findings described in the present review make it highly feasible been used to increase autophagy activity have proven to be that autophagy is also playing a crucial role in the damage of livers beneficial in decreasing liver injury and cell death (Pantazi affected by the other metabolic diseases and that are submitted to et al., 2015; Nakamura et al., 2018, 2019; Wang J. et al., 2020). surgery. As will be seen below, reports remain very limited and Only one study revealed that pharmacological inhibition of denote a huge area of opportunity in the field of liver surgery with autophagy protected optimal grafts undergoing transplantation underlying pathological conditions. (Gotoh et al., 2009). However, it should be noted that in Experimentally, modulation of autophagy through various this study, the autophagy and liver injury parameters were strategies protects livers affected by NAFLD and subjected to evaluated after very short reperfusion periods (15 or 120 min) I/R intrinsic to resections. Lithium chloride-induced autophagy in comparison with the rest of the studies (6 to 24 h). In via modulating both glycogen synthase kinase 3 beta (GSK3b) Frontiers in Cell and Developmental Biology | www.frontiersin.org 11 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 1 | Outcomes about the role of autophagy in normothermic hepatic I/R injury, in the last 5 years. Study Animal Type of liver Ischemia Reperfusion Parameters of Modulation of Results from species time time autophagy in autophagy autophagy normothermic modulation vs. ischemia without untreated groups modulation Lee et al., 2016 Hepatocytes Optimal 1h 0, 1, 3, 5, and Autophagy Yes. Everolimus. Autophagy from AML12 24 h parameters vs. enhancement: ↑LC3 I cell line Control group: ↓LC3 I to LC3 II conversion, to LC3II conversion, ↓p62. Cell injury: ↓Atg5. ↑mTOR ↓Apoptosis. phosphorylated. Biel et al., 2016 C57BL/6 mice Optimal 4h 1 and 2 h Autophagic Yes. SIRT1 Autophagy primary parameters vs. overexpression enhancement: ↑LC3 I hepatocytes Control group: Mild to LC3 II conversion, ↑LC3 I to LC3 II ↑Autophagosomes conversion. No number. ↑Mitophagy: expression of SIRT1 Improved mitochondria structure and function. Cell injury: ↓Cell death percentage. Xu D. et al., C57BL/6 mice Optimal 4h 2h Autophagy Yes. CDDO Autophagy 2017 primary parameters vs. imidazole, a Nrf2 enhancement: ↑LC3 I hepatocytes Control group: Mild activator. to LC3 II conversion, ↑LC3 I to LC3 II ↑Autophagosomes conversion, mild number, ↓SQSTM1. ↑SQSTM1. ↓Mitochondrial ↑Autophagosomes dysfunction. Cell injury: number. ↓Cytotoxicity percentage, ↓Apoptosis. Khader et al., H4IIE Optimal 4 and 6 h 2, 4, and 24 h Autophagy Yes. SRT1720, a Autophagy 2017 hepatoma cells parameters vs. SIRT1 activator. enhancement: ↑LC3 I and Sprague- Control group: ↓LC3 I to LC3 II conversion, Dawley rat to LC3 II conversion. ↓SQSTM1. primary ↓Mitochondrial hepatocytes dysfunction. Cell injury: ↑Cell survival. Cui et al., 2018 Hepatocytes Optimal 90 min 12 h Autophagy Yes. Interferon Autophagy inhibition: from AML12 parameters: Notable regulatory factor-1 ↓LC3 and ↓Beclin-1 cell line LC3 and Beclin-1 siRNA or expression. expression. Glycyrrhizin Acid, an HMGB1 inhibitor. Kong et al., C57BL/6 mice Optimal 4h 2h Autophagy Yes. SB216763, Autophagy 2019 primary parameters: Mild LC3 inhibitor of GSK3β. enhancement: ↑LC3 I hepatocytes I to LC3 II conversion to LC3 II conversion, and ATG5 ↑ATG5. ↓mTOR expression. Notable phosphorylated. Cell expression of mTOR injury: ↓Cytotoxicity phosphorylated. percentage. Li J. et al., 2020 C57BL/6 mice Optimal Not specified. Not specified. Autophagy Yes. CD5-like Autophagy primary parameters vs. Sham (CD5L) protein, an enhancement: ↑LC3 I hepatocytes group: ↓ LC3 I to LC3 apoptosis inhibitor to LC3 II conversion, II conversion, ↓ATG7. of macrophage. ↑ATG7. Cell injury: ↓Apoptosis, ↓Oxidative stress. Bi et al., 2020 Sprague- Aged 1h 8h Autophagy Yes. Irisin. Autophagy Dawley rat hepatocytes parameters vs. enhancement: ↑LC3 I primary Control old group: to LC3 II conversion, hepatocytes Mild ↑LC3 I to LC3 II ↓p62. conversion and mild ↓p62. (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 12 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 1 | Continued Study Animal Type of liver Ischemia Reperfusion Parameters of Modulation of Results from species time time autophagy in autophagy autophagy normothermic modulation vs. ischemia without untreated groups modulation Lee et al., 2016 BALB/c mice. Optimal Partial 24 h Autophagy Yes. Everolimus. Autophagy normothermic parameters vs. Sham enhancement: ↑ LC3B, ischemia group: ↓LC3B, mild ↓p62. Liver damage: (right lateral ↑p62. ↓ALT and AST, lobe). 45 min ↓Necrosis, ↓Apoptosis, ↓Inflammation. Li M. et al., C57BL/6 mice Optimal Partial 6 and 12 h Autophagy Yes. Alda-1, an Autophagy 2018 normothermic parameters vs. Sham activator of ALDH2. enhancement: ↑LC3 I ischemia group: No changes in to LC3 II conversion, (right lateral LC3 I to LC3II ↑Autophagosomes lobe). 90 min conversion or number, ↓p62. Liver autophagosomes damage: ↓ALT and number, mild ↑p62. AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Xiang et al., Balb/c mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Bergenin. Autophagy inhibition: 2020 normothermic parameters vs. Sham ↓Beclin-1, ↓LC3-II, ischemia of group: ↑Beclin-1, ↑p62. Liver damage: 70% (left and ↑LC3-II, ↓p62. ↓ALT and AST, middle ↓Necrosis, ↓Apoptosis, Lobes). 1 h ↓Inflammation, ↓Oxidative stress. Ji et al., 2020 BALB/c mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Cafestol, a Autophagy inhibition: normothermic parameters vs. Sham natural diterpene ↓Beclin-1, ↓LC3, ↑p62. ischemia of group: ↑Beclin-1, extract from coffee Liver damage: ↓ALT 70% (left and ↑LC3, ↓p62. beans. and AST, ↓Necrosis, middle lobes). ↓Apoptosis, 45 min ↓Inflammation. Tan et al., 2018 C57BL/6 mice Optimal Partial 6h Autophagy Yes. Helix B surface Autophagy normothermic parameters: Mild LC3 peptide, an enhancement: ↑LC3 I ischemia of I to LC3 II conversion erythropoietin to LC3 II conversion, 70% (left and and Beclin-1 -derived peptide. ↑Beclin-1, middle lobes). expression. Low ↑Autophagosomes 1h number of number. Liver damage: autophagosomes. ↓ALT and AST, Notable expression of ↓Necrosis, ↓Apoptosis. phosphorylated mTOR. Li H. et al., Sprague- Optimal Partial 6h Autophagy Yes. N-acetyl-L- Autophagy inhibition: 2020 Dawley normothermic parameters vs. Sham tryptophan, a ROS ↓LC3, ↓Beclin-1, ↓ rats ischemia of group: ↑LC3, scavenger. ATG-7, ↑p62. 70% (left and ↑Beclin-1, ↑ATG-7, ↓Mitophagy: Improved middle lobes). ↓p62. Affected mitochondria 45 min mitochondrial morphology. structure. Kong et al., C57BL/6 mice Optimal Partial 6h Autophagy Yes. SB216763, an Autophagy 2019 normothermic parameters vs. Sham inhibitor of GSK3β. enhancement: ↑LC3 I ischemia group: ↑LC3 I to LC3 to LC3 II conversion, (cephalad II conversion, ↑ATG5, ↑ATG5, lobes). ↑Autophagosomes ↑Autophagosomes 90 min number. ↑mTOR number. ↓ mTOR phosphorylated. phosphorylated. Liver damage: ↓ALT and AST, ↓Necrosis, ↓Apoptosis. (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 13 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 1 | Continued Study Animal Type of liver Ischemia Reperfusion Parameters of Modulation of Results from species time time autophagy in autophagy autophagy normothermic modulation vs. ischemia without untreated groups modulation Wu et al., 2017 Balb/c mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Quercetin. Autophagy inhibition: normothermic parameters vs. Sham ↓Beclin-1, ↓LC3, ↑p62. ischemia of group: ↑Beclin-1, Liver damage: ↓ALT 70% (left and ↑LC3, ↓p62. and AST, ↓Necrosis, middle lobes). ↓Apoptosis, 45 min ↓Inflammation. Biel et al., 2016 C57BL/6 mice Optimal Total hepatic 20 min Autophagy Yes. SIRT1 Autophagy ischemia. parameters vs. overexpression enhancement: ↑LC3 I 45 min Control group: ↓LC3 I to LC3 II conversion. to LC3 II conversion. ↑Mitophagy: Improved ↓SIRT1 mitochondria function. Liu et al., 2020 Sprague- Optimal Partial 6 and 24 h Autophagy Yes. Alda-1, an Autophagy Dawley normothermic parameters vs. Sham activator of ALDH2. enhancement: ↑LC3 I rats ischemia of group: ↓LC3 I to LC3 to LC3 II conversion, 70% (left and II conversion, ↓ ↑ATG7, ↓p62. ↓mTOR middle lobes). ATG7, ↑p62. ↑mTOR phosphorylated Liver 1h phosphorylated. damage: ↓ALT and AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Yang et al., C57BL/6 mice Optimal Partial 6h Autophagy Yes. Vitamin D Autophagy 2015 normothermic parameters vs. Sham enhancement: ↑LC3 I ischemia of group: Mild ↑LC3I to to LC3 II conversion, 70% (left and LC3II conversion, ↑Beclin-1, ↑ATG7, middle lobes). mild ↑Beclin-1, mild ↑autophagic vacuoles. 1h ↑ATG7 and mild Liver damage: ↓ALT ↑Autophagic and AST, ↓Necrosis, vacuoles. ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Chen et al., Balb/c mice Optimal Partial 6, 12, and 24 h Autophagy Yes. 15-Deoxy- Autophagy inhibition: 2017a normothermic parameters vs. Sham 112,14- ↓LC3 I to LC3 II ischemia of group: ↑LC3I to LC3II prostaglandin J2, a conversion, ↓Beclin-1. 70% (left and conversion, dehydration Liver damage: ↓ALT middle lobes). ↑Beclin-1. product of and AST, ↓Necrosis, 1h prostaglandin D2. ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Feng et al., Balb/c mice Optimal Type of 2, 8, and 24 h Autophagy Yes. Salidroside, Autophagy inhibition: 2017 normothermic parameters vs. Sham main active ↓LC3 I to LC3 II ischemia not group: ↑LC3 I to LC3 component of conversion, ↓Beclin-1, specified. II conversion, Rhodiola rosea. ↑p62, 45 min ↑Beclin-1, ↓p62, ↓Autophagosomes ↑Autophagosomes formation. ↑mTOR formation. ↓mTOR phosphorylated Liver phosphorylated damage: ↓ALT and AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation. Deng et al., Balb/c mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Beraprost Autophagy inhibition: 2018 normothermic parameters vs. Sham sodium, an analog ↓LC3 I to LC3 II ischemia of group: ↑LC3 I to LC3 of prostacyclin. conversion, ↓Beclin-1, 70% II conversion, ↑p62. Liver damage: (ischemic ↑Beclin-1, ↓p62. ↓ALT and AST, lobes not ↓Necrosis, ↓Apoptosis, specified). ↓Inflammation. 45 min (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 14 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 1 | Continued Study Animal Type of liver Ischemia Reperfusion Parameters of Modulation of Results from species time time autophagy in autophagy autophagy normothermic modulation vs. ischemia without untreated groups modulation Cui et al., 2018 C57BL/6 mice Optimal Partial 2, 6, 12, and Autophagy Yes. Knockout of Autophagy inhibition: normothermic 24 h parameters vs. Sham Interferon ↓LC3 I to LC3 II ischemia of group: ↑LC3 I to LC3 regulatory factor-1. conversion, 70% (left and II conversion, ↓Autophagosomes middle lobes). ↑Autophagosomes number. Liver damage: 90 min number. ↓ALT and AST, ↓Necrosis. Kou et al., 2020 Sprague Optimal Partial 6h Autophagy Yes. Glycyrrhizin, Autophagy inhibition: Dawley rats normothermic parameters vs. Sham an HMGB1 ↓LC3 I to LC3 II ischemia of group: ↑LC3 I to LC3 inhibitor. conversion, ↓Beclin-1. 70% (left and II conversion, Liver damage: ↓ALT middle lobes). ↑Beclin-1. and AST, ↓Necrosis, 90 min ↓Apoptosis, ↑NO, ↓Endothelin-1, ↓Inflammation, ↓Oxidative stress. Yu et al., 2019 BALB/c mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Levo- Autophagy inhibition: normothermic parameters vs. Sham tetrahydropalmatine ↓LC3, ↓Beclin-1. Liver ischemia of group: ↑LC3 and (L-THP), an active damage: ↓ALT and 70% ↑Beclin-1. component of AST, ↓Necrosis, (ischemic Corydalis ↓Apoptosis, lobes not yanhusuo. ↓Inflammation. specified). 45 min Dusabimana C57BL/6 mice Optimal Partial 5h Autophagy Yes. Nobiletin, a Autophagy et al., 2019) normothermic parameters vs. Sham natural flavonoid. enhancement: ↑LC3 I ischemia of group: No changes in to LC3 II conversion, 70% (left and LC3 I to LC3 II ↑ATG5, ↑ATG12, middle lobes). conversion or ATG5. ↓p62. ↑SIRT1/FOXO3a 1h ↓ATG12, ↑p62. Liver damage: ↓ALT ↓SIRT1/FOXO3a and AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Xu D. et al., C57BL/6 mice Optimal Partial 6 and 12 h Autophagy Yes. CDDO Autophagy 2017 normothermic parameters vs. Sham imidazole, a Nrf2 enhancement: ↑LC3 I ischemia of group: Mild ↑LC3 I to activator. to LC3 II conversion, 70% LC3 II conversion, ↑Autophagosomes (cephalad ↑Autophagosomes number, ↓SQSTM1. lobes). number, ↑SQSTM1. Liver damage: ↓ALT 90 min and AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Wang et al., BALB/c mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Oleanolic Acid. Autophagy inhibition: 2019 normothermic parameters vs. Sham ↓LC3 I to LC3 II ischemia of group: ↑LC3 I to LC3 conversion, ↓Beclin-1. 70% (left and II conversion, Liver damage: ↓ALT middle lobes). ↑Beclin-1. and AST, ↓Necrosis, 1h ↓Apoptosis. Xu S. et al., Balb/c mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Propylene Autophagy inhibition: 2017 normothermic parameters vs. Sham glycol alginate ↓LC3 II, ↓Beclin-1, ischemia of group: ↑LC3 II, sodium sulfate, a ↑p62. Liver damage: 70% ↑Beclin-1, ↓p62. polysaccharide ↓ALT and AST, (ischemic isolated from brown ↓Necrosis, ↓Apoptosis, lobes not algae. ↓Inflammation. specified). 45 min (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 15 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 1 | Continued Study Animal Type of liver Ischemia Reperfusion Parameters of Modulation of Results from species time time autophagy in autophagy autophagy normothermic modulation vs. ischemia without untreated groups modulation Liu H. et al., C57BL/6 mice Optimal Partial 8, 12, and 24 h Autophagy Yes. Spermidine Autophagy 2019 normothermic parameters vs. Sham enhancement: ↑LC3 I ischemia of group: Mild ↑LC3 I to to LC3 II conversion, 70% (left and LC3 II conversion, ↑Beclin-1, middle lobes). mild ↑Beclin-1 and ↑Autophagic vacuoles 1h mild ↑Autophagic number. ↑ULK-1 vacuoles number. phosphorylated, Mild ↑AMPK ↓mTOR phosphorylated, Mild phosphorylated. Liver ↑ULK-1 damage: ↓ALT and phosphorylated. AST, ↓Necrosis, ↑mTOR ↓Apoptosis, phosphorylated. ↓Inflammation. Li J. et al., 2017 BALB/C mice Optimal Partial 2, 8, and 24 h Autophagy Yes. Fucoidan. Autophagy inhibition: normothermic parameters vs. Sham ↓LC3 I to LC3 II ischemia of group: ↑LC3 I to LC3 conversion, ↓Beclin-1, 70% (left and II conversion, ↑p62, middle lobes). ↑Beclin-1, ↓p62, ↓Autophagosomes 1h ↑Autophagosomes and Autolysosomes and Autolysosomes number. Liver damage: number. ↓ALT and AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation. Miyauchi et al., C57BL/6 mice Optimal Partial 1, 3, and 6 h Autophagy Yes. 12-h fasting Autophagy 2019 normothermic parameters: Mild β-hydroxybutyric enhancement: ↑LC3B ischemia of LC3B expression. acid ↑FOXO1/3 Liver 70% (left and Mild FOXO1/3 damage: ↓ALT, middle lobes). expression. ↓Necrosis, 1h ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Bai et al., 2018 Bama miniature Optimal Partial 3 h, 1 and Autophagy Yes. Hydrogen-rich Autophagy inhibition: pigs. normothermic 3 days parameters vs. Sham saline. ↓LC3B, ↓Beclin-1, ischemia group: ↑LC3B, ↑p62. ↑mTOR Liver combined ↑Beclin-1 ↓p62. damage: ↓ALT and with partial ↓mTOR AST, ↓Oxidative stress. resection. Ischemia time: 1 h Khader et al., C57BL/6 mice Optimal Partial 24 h Autophagy Yes. SRT1720, a Autophagy 2017 normothermic parameters vs. SIRT1 activator. enhancement: ↑LC3 I ischemia of Control group: No to LC3 II conversion, 70% (left and changes in LC3 I to ↓SQSTM1. Liver middle lobes). LC3 II conversion or damage: ↓ALT and 1h SQSTM1. AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation, ↓Oxidative stress. Jiang et al., C57BL/6 mice Aged livers Partial 6h Autophagy Yes. Ischemic Autophagy 2019 normothermic parameters vs. Sham preconditioning enhancement: ↑LC3 I ischemia of group: ↓ LC3 I to combined with to LC3 II conversion, 70% LC3 II conversion and Rapamycin. ↓p62. Liver damage: (cephalad ↑p62. ↓ALT, ↓Necrosis, lobes). ↓Apoptosis 90 min (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 16 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 1 | Continued Study Animal Type of liver Ischemia Reperfusion Parameters of Modulation of Results from species time time autophagy in autophagy autophagy modulation normothermic vs. untreated groups ischemia without modulation Bi et al., 2020 Sprague- Aged liver Partial 24 h Autophagy Yes. Irisin. Autophagy enhancement: Dawley normothermic parameters vs. Sham ↑LC3 I to LC3 II rats ischemia of old group: ↑LC3 I to conversion, ↓p62. Liver 70% LC3 II conversion and damage: ↓ALT, (ischemic ↓p62. ↓Necrosis, ↓Apoptosis, lobes not ↓Inflammation, specified). ↓Oxidative stress. 60 min Cho et al., C57BL/6 mice Alcoholic fatty Partial 5h Autophagy Yes. Autophagy enhancement: 2017 liver normothermic parameters vs. Sham 2-Methoxyestradiol ↑LC3 I to LC3 II ischemia of group: ↓LC3 I to LC3 conversion, ↑ATG3, 70% (left and II conversion, ↓ATG3, ↑ATG7, ↑ATG12-5, middle lobes). ↓ATG7, ↓ATG12-5, ↓p62, ↑LAMP-2 1h ↑p62, ↓LAMP-2, ↑Autophagic vacuoles ↓Autophagic number. ↑Mitophagy: vacuoles number. ↓PINK1 and ↑Parkin ↓Mitophagy: ↑PINK1 ↑SIRT1 Liver damage: and ↓Parkin. ↓SIRT1 ↓ALT and AST, ↓Necrosis, ↓Inflammation, and extracellular signal-regulated kinase (ERK) 1/2 pathways occurring in each of these different experimental conditions must was beneficial for steatotic livers undergoing I/R (Kan et al., be characterized. 2017). A therapeutic effect was also achieved by treatment Very few experimental studies have evaluated the role of with exogenous hydrogen sulfide, which reduced ER stress and autophagy in transplantation of NAFLD grafts (Gracia-Sancho the class A scavenger receptor (SRA) pathway, and promoted et al., 2013; Zaouali et al., 2013a,b, 2017; Panisello-Roselló et al., autophagy. This led to the amelioration of hepatic damage 2017, 2018; Zhang et al., 2019). To date, reported results differ by reducing oxidative stress and inflammation (Ruan et al., depending on the experimental model used. Most of the studies 2019). Ischemic preconditioning, a surgical therapeutical strategy on steatotic liver grafts have used an ex vivo reperfusion model. consisting of a short period of ischemia followed by a brief In these conditions, when autophagy parameters were analyzed period of reperfusion before a sustained ischemic insult, proved after short reperfusion periods (1 to 2 h), results agreed with beneficial in a mouse model of I/R injury in steatotic livers, those reported in optimal liver grafts: (a) cold ischemia induces by increasing autophagic flux. This surgical technique restored a mild increase or no change in autophagy parameters; and (b) mitochondrial function via heme oxygenase-1 (HO-1)-mediated grafts benefited from pharmacological strategies that increased autophagy and protected against damage (Liu et al., 2016). Such autophagy activity (Gracia-Sancho et al., 2013; Zaouali et al., outcomes mean that pharmacological treatments that stimulate 2013b, 2017). However, results were altogether different in the autophagy could be potentially useful in livers affected by only study conducted in an in vivo model, since autophagy metabolic diseases and that are subjected to surgery. Accordingly, parameters after a prolonged reperfusion period (6 h), increased another study revealed that calpain 2 inhibition enhanced as a result of I/R injury. Furthermore, under these conditions, the autophagy, decreased mitochondrial dysfunction, suppressed cell pharmacological inhibition of autophagy protected steatotic liver death, and improved injury in livers affected by NAFLD and grafts. This study also generated another important result in the obesity and undergoing I/R (Zhao et al., 2016). However, it should setting of transplantation: in steatotic grafts, berberine inhibited be mentioned that opposite results have also been described in autophagy and protected the graft, but the same drug activated HFD-fed mice exposed to I/R, since treatment with Exendin autophagy in optimal grafts and decreased liver injury (Lin et al., 4, a glucagon-like peptide 1 analog, mitigated autophagy thus 2017; Zhang et al., 2019). This observation underscores the very ameliorating hepatocellular injury, and preserving mitochondrial different signaling mechanisms that act in optimal vs. steatotic integrity (Gupta et al., 2014). These controversies could be caused grafts, despite being subjected to the same surgical maneuvers. by the great diversity of experimental conditions described in the As to the role of autophagy among the mechanisms literature in warm I/R models, such as different times of ischemia responsible for liver injury-induced hyperglycemia, reports in the or reperfusion, induction of ischemia in different liver regions, literature are scarce. In a streptozotocin-induced hyperglycemic or various ways of inducing steatosis. To reach a consensus on mouse model, hyperglycemia aggravated thioacetamide-induced the most convenient way to modulate autophagy in liver surgery acute liver injury. In this model, the inflammatory response in the presence of NAFLD, the effects of I/R on autophagy was stimulated by promoting liver resident macrophage Frontiers in Cell and Developmental Biology | www.frontiersin.org 17 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 2 | Findings about the involvement of autophagy in liver transplantation. Study Animal Type of liver Cold Reperfusion Parameters of Modulation of Results from species graft preservation time autophagy in autophagy autophagy modulation time transplantation vs. untreated groups without modulation Pantazi et al., Male SD rats Optimal 8h 24 h Autophagy YES. Trimetazidine Autophagy 2015 grafts parameters vs. Sham added to IGL-1 enhancement: ↑ LC3B group: No changes in preservation and ↑Beclin-1. LC3B or Beclin-1. solution. ↑SIRT1/FOXO1 pathway Mild ↑SIRT1/FOXO1 activity, ↓mTOR activity. pathway activity. No Liver damage: ↓ALT, changes in mTOR ↓Oxidative stress. activity. Nakamura C57BL/6 mice Optimal 18 h in mice 6h Autophagy YES. Antibiotic Autophagy et al., 2019 grafts in mice parameters: Mild LC3 pretreatment in enhancement: ↑LC3 I to I to LC3II conversion. recipient to LC3 II conversion. ↓ ↑ p-S6K (mTORC1 modulate gut p-S6K (mTORC1 activity) activity) and ↑CHOP microbiome. and ↓ER stress (CHOP). (ER stress marker). Liver damage: ↓AST, ↓Necrosis, ↓Apoptosis, ↓Inflammation. Xue et al., 2020 C57BL/6 mice Optimal graft 20 h 6h Autophagy YES. Pituitary Autophagy parameters vs. Sham adenylate enhancement: ↑LC3 I to group: ↓LC3 I to cyclase-activating LC3 II conversion, LC3II conversion, polypeptide ↑ATG5, ↑Beclin-1, ↑ATG5 ↑Beclin-1, no (PACAP). ↓p62. Liver damage: ↑ changes in p62. Survival rate, ↓ALT, ↓Necrosis. Nakamura C57BL/6 mice Optimal 20 h 6h Autophagy markers: YES. Heme Autophagy et al., 2018 grafts in mice Mild expression of oxygenase-1 enhancement: ↑LC3B. LC3B and SIRT1. overexpression. ↑SIRT1. Liver damage: ↓ALT, ↓Necrosis, ↓Apoptosis, ↓Inflammatory mediators. Gotoh et al., Wistar rats Optimal 24 h 15 and 120 min Autophagy markers: YES. Wortmannin, Autophagy inhibition: 2009 grafts Detected LC3 and a PI3K inhibitor. ↓LC3, ↓Number of nascent nascent autophagosomes autophagosomes and and autolysosomes, autolysosomes volume at 15 min of density, at 15 min of reperfusion. reperfusion. Liver damage: ↓ALT and AST at 120 min of reperfusion, ↑ Survival rate. Wang J. et al., SD rats Optimal graft Not specified. 24 h Autophagy YES. Autophagy 2020 parameters vs. Sham Suberoylanilide enhancement: ↑LC3 I to group: No changes in hydroxamic acid LC3 II conversion, LC3 I to LC3II (SAHA), a ↑ATG5, ↑ATG16L1, conversion, ATG5 or pan-histone ↓p62. ↓AKT/mTOR Liver ATG16L1. ↑p62. deacetylase damage: ↓ALT and AST, ↑AKT/mTOR inhibitor. ↓Apoptosis, ↓Inflammatory cytokines. Lin et al., 2017 Wistar rats Optimal Not specified 6h Autophagy YES. Berberine. Autophagy grafts parameters vs. Sham enhancement: ↑LC3 I to group: Mild ↑LC3 I to LC3 II conversion, LC3 II conversion, ↑Beclin-1, ↓p62. ↑Beclin-1, mild ↓p62. ↑SIRT1/FoxO3α Mild ↑SIRT1/FoxO3α pathway activity. Liver pathway activity. damage: ↓ALT and AST, ↓Apoptosis, ↓Oxidative stress. (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 18 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 2 | Continued Study Animal Type of liver Cold Reperfusion Parameters of Modulation of Results from species graft preservation time autophagy in autophagy autophagy time transplantation modulation vs. without modulation untreated groups Chen et al., Lewis rats as Optimal grafts 35 min 14 days Autophagy YES. 3-Methyladenine, Autophagy inhibition: 2019b donors and parameters vs. an autophagy inhibitor. ↓LC3 I to LC3 II Brown Norway syngeneic control: conversion in CD8 + T rats as ↑LC3 I to LC3 II cells. Liver damage: recipients. conversion in ↓ALT and AST, CD8 + T cells. ↓Rejection index, ↑ Survival rate. Wang R. R. Lewis rats as Reduced-size Not specified 0, 1, 3, 5, 7, Autophagy YES. HO-1 transduced Autophagy et al., 2017 donors and liver grafts. and 14 days parameters: Mild LC3 Bone-marrow derived enhancement: ↑LC3 I Brown Norway I to LC3 II conversion Mesenchymal Stem to LC3 II conversion, rats as and Beclin-1 Cells. ↑Beclin-1. ↓mTOR recipients. expression. Notable phosphorylated. Liver expression of damage: ↓Rejection phosphorylated index, ↓Apoptosis. mTOR. Zeng et al., C57BL/6 mice Grafts from 4h 2h Autophagy YES. HOPE Autophagy 2019 donation after parameters vs. (Hypothermic enhancement: circulatory control: Mild oxygenated machine ↑LC3B-II,↑ULK1, death (DCD). ↑LC3B-II ULK1, mild perfusion) treatment ↑Atg5 and ↓p62. ↑Atg5 and mild during 1 h ↓mTOR. Liver damage: ↓p62. ↓mTOR. Not ↓ALT and AST, ↓ statistical Necrosis and significance. Apoptosis, ↓Oxidative stress. Liu T. et al., Sprague Grafts from Not specified 6, 12, and 24 h Autophagy NO. N/A 2019 Dawley rats. DCD. parameters at 6, 12, and 24 h of reperfusion in rats: Notable increased expression of LC3 and AMPK. Notable decreased expression of p62. Zhang et al., Wistar rats fed Steatotic grafts. Not specified 6h Autophagy YES. Berberine. Autophagy inhibition: 2019 with high-fat Not additional parameters vs. ↓LC3 I to LC3 II diet for data about steatotic sham: ↑LC3 conversion, ↓Beclin-1, 12 weeks. presence of I to LC3 II conversion, ↓p62, metabolic ↑Beclin-1, ↑p62, ↓Autophagosomes comorbidities. ↑Autophagosomes number. ↓ER stress number. ↑ER stress (p-PERK, CHOP, Bip). (p-PERK, CHOP, Bip). Liver damage: ↓ALT and AST, ↓Necrosis, ↓Oxidative stress, ↓Inflammatory cytokines. Panisello- Zucker rats Steatotic grafts. 24 h Not Autophagy YES. IGL-1 Autophagy Roselló et al., Obesity. reperfusion. parameters vs. preservation solution. enhancement: ↑ 2018 Liver samples steatotic sham: No LC3B,↑Beclin-1, collected at the changes in, LC3B, ↑ATG7. ↓mTOR end of cold Beclin-1 or ATG7. activity. Liver damage: storage. ↓mTOR activity ↓ALT and AST, ↓Necrosis, ↓Apoptosis. Gracia-Sancho Wistar rats fed Steatotic grafts. 16 h 1 h (ex vivo Autophagy YES. Simvastatin. Autophagy et al., 2013 with high-fat Not additional reperfusion) parameters vs. enhancement: ↑LC3 I diet for 3 days. data about steatotic control: Mild to LC3 II conversion. presence of ↓LC3 I to LC3 II Liver damage: ↓ALT metabolic conversion. and AST. comorbidities. (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 19 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 2 | Continued Study Animal Type of liver Cold Reperfusion Parameters of Modulation of Results from autophagy species graft preservation time autophagy in autophagy modulation vs. untreated time transplantation groups without modulation Zaouali et al., Zucker rats Steatotic grafts. 24 h 2 h (ex vivo Autophagy YES. Trimetazidene Autophagy enhancement: 2017 Obesity. reperfusion) parameters vs. added to IGL-1 ↑LC3 I to LC3 II steatotic control: No preservation solution. conversion, ↑Beclin-1. changes in LC3 I to ↑SIRT1. Liver damage: LC3 II conversion, ↓ALT and AST ↓TNFα. Beclin-1 No changes in SIRT1. Zaouali et al., Zucker rats Steatotic grafts. 24 h 2 h (ex vivo Autophagy YES. Trimetazidene + Autophagy enhancement: 2013b Obesity. reperfusion) parameters vs. Melatonin added to ↑LC3 I to LC3 II steatotic control: Mild IGL-1 preservation conversion, ↑Beclin-1, ↑LC3 I to LC3 II solution. ↑ATG7, ↓p62. ↓ER stress conversion, (GRP78, CHOP, p-PERK). ↑Beclin-1, ↑p62. Liver damage: ↓ALT and ↑ER stress (GRP78, AST, ↓Oxidative stress. CHOP, p-PERK). Minor et al., German Optimal grafts. 10 h 1 h, 7 days Autophagy YES. Hypothermic Autophagy enhancement: 2011 landrace pigs parameters: Mild LC3 reconditioning by ↑LC3-II, ↑Beclin-1, at 1 h of II and Beclin-1 gaseous oxygen reperfusion. Liver damage: expression, at 1 h of persufflation treatment ↓ALT ↑ Survival rate, at reperfusion. during 2 h. 7 days after transplantation. Liu T. et al., Bama miniature Grafts from Not specified 6, 12, and 24 h Autophagy NO. N/A 2019 pigs DCD. parameters at 24 h of reperfusion in pigs: Notable increased expression of LC3 and AMPK. Notable decreased expression of p62. Nakamura Humans Grafts from 7–8 h on 2h Autophagy YES. Autophagy enhancement: et al., 2019 donors after average parameters: Mild Pre-transplantation ↑LC3B. ↓ER stress brain or cardiac LC3B expression. Antibiotics (CHOP). Liver damage: death. Notable CHOP treatment ≥ 10 days in ↓ALT and AST. expression. recipients. Chen et al., Humans Liver transplant Not specified Not specified Autophagy NO N/A 2019b recipients with parameters vs. acute rejection. recipients without acute rejection: ↑LC3 expression in CD8 + T cells. Nakamura Humans Not specified Not specified 2 h after portal Autophagy markers: NO N/A et al., 2018 reperfusion Expression of LC3B and SIRT1. Ricca et al., Humans Grafts from 5 to 10 h ≤2 h after Autophagy markers: YES. Ischemic Autophagy enhancement: 2015 donors after reperfusion Expression of LC3. postconditioning. ↑LC3. Liver damage: ↓I/R brain death, injury at reperfusion biopsy, including defined by the presence of steatotic and both inflammatory non-steatotic infiltration and liver grafts. hepatocellular necrosis. Degli Esposti Humans Grafts from 5 to 10 h Not specified Steatotic grafts YES. Ischemic Steatotic grafts Autophagy et al., 2011 donors after (liver samples Autophagy markers: preconditioning. enhancement: ↑LC3, brain death, collected Expression of LC3 ↑Beclin-1. Liver damage: including before and Beclin-1. No changes in steatotic and abdomen Non-steatotic grafts transaminases, ↓Acute non-steatotic closure). Autophagy markers: rejection. liver grafts. Rarely observed LC3 Non-steatotic grafts No o Beclin-1 changes in autophagy expression. parameters. Liver damage: ↓ALT and AST in non-steatotic grafts. Frontiers in Cell and Developmental Biology | www.frontiersin.org 20 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome NLRP3 inflammasome activation and inhibiting AMPK/mTOR these conditions. The combination of several of these conditions autophagy signaling pathways. Autophagy restoration by AMPK is commonplace in clinical practice, due to their high prevalence. activation or mTOR knockdown inhibited NLRP3 inflammasome In those multiple disease scenarios, autophagy most likely plays activation in Kupffer cells and decreased thioacetamide-induced a predominant role since it contributes to the development of acute liver injury in hyperglycemic mice (Wang Q. et al., each of these pathological entities when manifested separately. 2020). Considering that the autophagy-NLRP3 inflammasome There are even some mediators of autophagy that are common pathway is also involved in NAFLD (Wan et al., 2016), perhaps to hepatic ischemia, steatosis, obesity, MetS, and diabetes, such the regulation of this signaling pathway could be useful to as ER stress, AMPK, MAPK, or oxidative stress. Importantly, it protect against damage in liver surgery with other metabolic should be taken into account that the effectiveness of treatments comorbidities in addition to hyperglycemia. could be different depending on the combination of metabolic Liver dysfunctions in the immediate postoperative period of comorbidities that occurs in each situation, given that a beneficial liver resection or transplantation, especially in livers affected by therapy for steatotic livers in presence of obesity or MetS, may underlying metabolic conditions, are still an unsolved problem. not be effective in the case of steatotic livers also suffering As the prevalence of metabolic diseases such as NAFLD, MetS, diabetes. This hypothesis is originated based on existing reports insulin resistance, obesity, or diabetes is increasing worldwide, showing that some therapies that have been described to reduce the development of therapeutic options in patients affected by hepatic I/R injury exhibit different effectiveness depending on these diseases and also undergo liver surgery are required. There the underlying pathological condition in the liver. By way of is no doubt that regulation of autophagy improves warm I/R example, therapies that have been found to reduce injury in injury in optimal livers, but is uncertain whether these benefits steatotic livers do not offer any benefit in non-steatotic grafts are maintained when livers affected by metabolic diseases face I/R (Álvarez-Mercado et al., 2019). Therefore, in order to consider injury. The relevance of autophagy steatotic liver transplantation the autophagy pathway as a possible therapeutic target in patients associated with other related metabolic comorbidities has not with several metabolic comorbidities and that are subjected been investigated. To date, in studied models of steatotic to transplantation or resection, autophagic molecular signaling liver transplantation, only some mention specifically that the must first be exquisitely characterized in experimental or clinical experimental animals were obese aside from harboring fatty models of fatty livers with obesity, diabetes, and/or MetS liver disease; and in all published studies, information on the (separately or in different combinations of these pathologies). parameters that would reflect the associated presence of insulin Much work is required before experimental results can be resistance or MetS in the animals is omitted. To the best of translated into clinical practice, and the first important step is our knowledge, the role of autophagy in experimental conditions to make use of experimental models that best mimic clinical in which the donor has steatosis and diabetes has not been conditions. In several experimental models of hepatic steatosis evaluated. Thus, in the coming years, research should be carried used nowadays, insulin resistance does not always develop, and out on autophagy and its associated molecular mediators in livers then insufficiently would reflect the pathogenesis of NAFLD undergoing surgery with one or more metabolic diseases, as it is in patients. There are several NAFLD animal models available, what happens in the clinical practice. So, concerning laboratory among which the most common are mice fed the MCD or approaches, to use experimental models the closest to clinical HFD. The MCD diet causes hepatic steatosis, and body weight practice is the best to design new therapeutic strategies to be loss but no insulin resistance. The HFD causes obesity, hepatic developed and successfully applied in patients. steatosis with mild injury, and insulin resistance. Genetically The lack of studies describing how metabolic diseases affect deficient ob/ob or db/db mice or Zucker rats, develop obesity and post-operative results of liver surgery in the medium and long steatosis, but in some cases, this does not occur automatically, term is evident, and even less is known to what extent autophagy and they often need to be fed either the MCD or the HFD is relevant in this setting. Intensive research is also necessary to (Adkins et al., 2013). Combinations of fat- and carbohydrate- establish whether autophagy is involved in post-surgical events rich dietary components have been used in rodents to mimic such as transient hyperglycemia and the development of MetS MetS. Among such diets, the “cafeteria” diet has been used to in liver transplantation recipients. This information will allow induce severe obesity with glucose intolerance and liver steatosis us to elucidate whether autophagy regulation could lead to the classifiable as NAFLD. After following the cafeteria diet for 8 generation of effective therapeutic strategies that could improve and 15 weeks, insulin resistance and high plasma triglyceride the current results of transplantation and resection, not only in levels are greater than in animals fed a traditional lard-based the immediate postoperative period but also in the long term. HFD (Parafati et al., 2015). It is important to characterize which metabolic comorbidities (obesity, MetS, diabetes, insulin resistance, fatty liver) are present or predominant in each Future Perspectives on Research in experimental model, in order to determine with greater accuracy Autophagy and I/R Injury, in Livers which combination of pathological entities to study when Affected by Metabolic Comorbidities submitting a fatty liver obtained from these models to liver To date, no experimental or clinical investigations have been surgery. Another highly relevant consideration when selecting carried out, in which the fatty liver undergoing surgery is an experimental model is to evaluate whether if it mimics combined with the presence of obesity, insulin resistance, MetS, clinical liver surgery. Regarding liver resection, there is a paucity and/or hyperglycemia, nor on the effects of autophagy under of research using experimental models that best mimic the Frontiers in Cell and Developmental Biology | www.frontiersin.org 21 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome ischemic times commonly used or including partial hepatectomy levels are harmful in non-steatotic liver grafts from brain dead in combination with vascular occlusion. Post-operative outcomes donor, which represents an experimental model very close to after liver resection are influenced by the magnitude of I/R injury, clinical practice (Álvarez-Mercado et al., 2019). Therefore, to but also by the regenerative response. Hepatic ischemia causes design effective strategies for protecting livers with metabolic liver injury and impairs regeneration, and these phenomena diseases and undergoing surgery, it is required to perform are further compromised if livers with underlying diseases meticulous research on the regulation of molecular mediators (steatosis, cirrhosis, diabetes, etc.) are resected and undergo I/R involved in both hepatic autophagy and I/R, using experimental injury (McCormack et al., 2007). In terms of modeling liver models that include NAFLD and even other metabolic diseases, transplantation, experimental studies have been carried out in the and that should be studied in diverse variants of liver surgery. absence of brain death or cardiac death, which means in surgical When attempting to develop new therapeutic strategies, one conditions very different to those occurring in clinical practice. should consider mediators that have been recently described to Brain death and cardiac death cause important hemodynamic modulate autophagy in obesity, NAFLD, or diabetes, but not changes, hypoperfusion in the mesenteric microcirculation and yet been studied in conditions in which one or more of these warm hepatic ischemia, which might result in significant comorbidities are combined with hepatic surgery. Table 3 shows modifications in the mediators generated in the liver, and some examples of this type of mediator. However, we must the concomitant inflammation. This could alter the autophagy consider that the regulation of autophagy could also cause serious pathways, and have deleterious effects on liver grafts used for side effects that would be a serious inconvenience in hepatic transplantation. It is necessary to include pathological liver grafts surgery. Recent studies have demonstrated that pharmacological in experimental studies, since the success, dysfunction or loss upregulation of autophagy decreases hepatotoxicity and steatosis of liver grafts may be affected by the presence of steatosis, in NAFLD. However, further studies are needed before autophagy diabetes, MetS, etc. in potential donors. These conditions should activation can be considered a viable treatment against I/R injury be considered in future research to establish how they influence in steatotic livers affected by other metabolic comorbidities, autophagy and post-operative outcomes. Since the effectiveness because upregulation of autophagy in hepatic stellate cells has of a therapeutic modality aimed at improving post-surgical been shown to foment their activation, and consequently, initiate outcomes in patients undergoing liver surgery could differ liver fibrosis. Inhibition of mTOR activity can induce autophagy, depending on the surgical conditions, the type and characteristics but also inhibits cell proliferation. Thus, in liver resection with of the liver and other factors, the use of experimental models vascular occlusion, cell proliferation is detrimental, since it that reproduce as closely as possible real clinical conditions precludes or impairs liver regeneration (Matter et al., 2014). is key to the effective translation of laboratory results into The liver responds to some stressors through global activation the clinical realm. of autophagy, causing lipid, protein, and organelle degradation; Several molecular mediators of autophagy in the steatotic but in some instances, upregulation of autophagy as a protective liver are key in hepatic I/R injury, which represents an area of mechanism against liver injury could only involve a specific opportunity to explore treatments for protecting livers affected form of autophagy, such as lipophagy. For instance, autophagy by metabolic diseases such as NAFLD, and those undergoing upregulated as the first line of defense against alcohol-induced surgery. AMPK and ER stress are closely related at the level toxicity in the liver, selectively targets mitochondria, and of molecular signaling mechanisms associated with autophagy LD, while excluding cytosolic proteins and other organelles. in NAFLD models (Homma and Fujii, 2020), as also occurs Future efforts should focus on establishing how selective forms in I/R. In fact, activation of AMPK, as well as inhibition of of autophagy can be individually modulated for therapeutic ER stress through drugs, are beneficial to regulate autophagy purposes (Singh and Cuervo, 2012). and protect steatotic livers that undergo surgery (Carrasco- Recent findings on autophagy signaling pathways in NAFLD Chaumel et al., 2005; Zaouali et al., 2013b), but its usefulness could also be useful in the development of markers for hepatic at the clinical level has not yet been evaluated. These findings injury progression. In NAFLD, lipolysosomes appear to reflect the indicate that regulation of AMPK and ER stress could be progressive impairment of lysosomal function, and particularly, promising therapies. On the other hand, although JNK and the capability of lysosomal hydrolases to catabolize fat. This ghrelin are also mediators involved in autophagy in fatty liver is supported by the correlation between an increase in the and I/R, their pharmacological modulation in livers with NAFLD number of lipolysosomes and disease activity, in terms of and undergoing surgery could lead to serious difficulties. In necroinflammation. Upregulation of lysosomal genes such as non-surgical NAFLD models, activation of JNK, or ghrelin is cathepsin D, LAMP1, LAMP2, Niemann-Pick-type C1 (NPC1), associated with activation of autophagy, which is beneficial vacuolar H + -ATPase, B2 subunit (ATP6V1B2), TFEB, suggests (Singh et al., 2009; Mao et al., 2015). However, it has been widely an increase in the overall lysosomal mass and could be interpreted demonstrated that JNK activation is implicated with steatotic as an attempt to counteract lysosomal dysfunction (Houben liver damage in transplantation, and warm ischemia alone or et al., 2017). Cathepsin D expression is greater in NAFLD combined with resection (Lehmann et al., 2003; Massip-Salcedo patients compared with controls, and a direct correlation et al., 2006; Ben Mosbah et al., 2010; Shaker et al., 2016; Li S. has been observed between cathepsin D expression and both et al., 2017); and, although pharmacological regulation of ghrelin NASH and fibrosis. Thus, molecular markers of lipophagy has been scarcely explored in liver surgery, first published reports impairment could help to identify hepatic injury in patients in this regard indicate that treatments increasing hepatic ghrelin on time (Carotti et al., 2020). Further studies are required Frontiers in Cell and Developmental Biology | www.frontiersin.org 22 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 3 | New promising autophagy regulators to be evaluated as therapeutical strategies in livers affected by metabolic diseases and submitted to surgery. Study Modulation of Type of liver Animal species or Experimental Results from administration of exogenous autophagy pathology cell culture model used to regulator of autophagy vs. untreated induce hepatic groups metabolic diseases Lee et al., 2020 Iridoids of Valeriana Steatotic cells Huh7 cells Treatment with oleic Autophagy enhancement: ↑LC3 I to LC3 II fauriei acid. conversion, ↑Autophagic vacuoles. ↑Lipophagy: ↓Lipid droplets. ↓mTORC1, ↓ULK1 phosphorylated. Other cellular effects: ↓Lipid accumulation. Valeriana fauriei Fatty liver, obesity. C57BL/6 J mice High fat diet for Autophagy enhancement: ↑LC3 I to LC3 II 70% ethanol 13 weeks. conversion, ↑Autophagic vacuoles. ↓mTOR extract phosphorylated, ↓ULK1 phosphorylated. Other liver effects: ↓Lipid accumulation, ↓Lipogenesis-related genes. Sinha et al., 2014 Caffeine Steatotic cells HepG2 cells Treatment with oleic Autophagy enhancement: ↑LC3 I to LC3 II acid and palmitic conversion, ↑ATG7, ↑ATG5, ↑Beclin, ↓p62 acid. ↑Autophagosome formation. ↓mTOR phosphorylated. Other cellular effects: ↑Lipid clearance. Caffeine Fatty liver C57BL6 mice High fat diet for Autophagy enhancement: ↑LC3 I to LC3 II 8 weeks. conversion, ↓p62. ↓mTOR phosphorylated. Other liver effects: ↓Lipid accumulation, ↑Lipid uptake in lysosomes, ↑Fatty acid β-oxidation Kuo et al., 2020 Magnolol Steatotic cells HepG2 cells and Treatment with Autophagy enhancement: ↑LC3 I to LC3 II C57BL/6 mice palmitic acid. conversion, ↑ATG7, ↓p62. ↓mTOR primary phosphorylated. Other cellular effects: ↓Cellular hepatocytes triglycerides, ↓Lipogenesis, ↑Lipolysis, ↓Inflammation. Magnolol Hypertriglyceri- Male Wistar Rats Tyloxapol Autophagy enhancement: ↑LC3 I to LC3 II demia conversion, ↑ATG5-12, ↑ATG7, ↑Beclin-1, ↓p62. ↓mTOR phosphorylated. Other liver effects: ↓Oxidative stress, ↓Lipogenesis, ↑Lipolysis, ↓Inflammation. Baldini et al., 2020 Silybin Steatotic cells Rat hepatoma FaO Treatment with oleic Autophagy inhibition: ↓LC3 I to LC3 II cells acid and palmitic conversion. Other cellular effects: ↓Lipid droplet acid. diameter. Wang C. et al., 2017 TFEB agonists: Fatty liver, C57BL/6J mice High fat diet for Autophagy enhancement: ↓p62. Other Digoxin, hyperglycemia, 1 month. metabolic and hepatic effects: ↓Circulating Ikarugamycin or hyperinsulinemia. glucose, ↓Circulating insulin, ↓Liver steatosis. Aloxidine dihydrochloride. Li X. et al., 2017 Pectic bee pollen Steatotic cells with HepG2 cells Treatment with high Autophagy enhancement: ↑LC3 I to LC3 II polysaccharide insulin resistance glucose and oleic conversion, ↓p62. Other cellular effects: acid and palmitic ↓Insulin resistance. acid. Pectic bee pollen Fatty liver, type 2 C57BL/6J mice High fat diet for Autophagy enhancement: ↑LC3 I to LC3 II polysaccharide diabetes. 8 weeks. conversion, ↓p62. ↓mTOR phosphorylated Other metabolic and hepatic effects: ↓Glucose intolerance, ↓Insulin resistance, ↓Liver steatosis, ↓AST, ↑Lipolysis. Gong et al., 2016 Akebia saponin D Steatotic cells Buffalo rat liver Treatment with oleic Autophagy enhancement: ↓LC3 I to LC3 II (BRL) cells acid. conversion, ↓Beclin, ↓p62, ↑Autolysosomes. ↓mTOR phosphorylated. Other cellular effects: ↓Lipid droplets. Akebia saponin D Fatty liver, insulin Ob/ob mice High fat diet. Autophagy enhancement: ↓LC3 I to LC3 II resistance. conversion, ↓Beclin, ↓p62, ↑Autophagosomes. Other metabolic and hepatic effects: ↓Circulating Glucose, ↓Circulating Insulin, ↓Insulin resistance, ↓Liver steatosis, ↓ALT and AST, ↓Apoptosis, ↓Oxidative stress. (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org 23 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome TABLE 3 | Continued Study Modulation of Type of liver Animal species or Experimental Results from administration of exogenous autophagy pathology cell culture model used to regulator of autophagy vs. untreated induce hepatic groups metabolic diseases Parafati et al., 2015 Bergamot Metabolic syndrome: Rcc:Han WIST rats Cafeteria diet (15% Autophagy enhancement: ↑LC3 I to LC3 II polyphenol fraction. Fatty liver, Obesity, protein, 70% conversion, ↑Beclin-1, ↓p62. ↑Lipophagy: Hyperglycemia, carbohydrates, ↓Lipid droplets. Other metabolic and hepatic Hypertriglyceridemia. 15% fat) for effects: ↓Circulating Glucose, ↓Circulating 13 weeks. Triglycerides, ↓Liver steatosis. Huang et al., 2017 Ginsenoside Rb2 Steatotic cells HepG2 cells and Treatment with high Autophagy enhancement: ↑LC3 I to LC3 II C57BL mice glucose and oleic conversion, ↓p62. ↑Lipophagy: ↓Lipid droplets. primary acid. ↑SIRT1 hepatocytes. Ginsenoside Rb2 Fatty liver, obesity, C57BL/KsJ-Lepdb N/A Autophagy enhancement: ↑LC3 I to LC3 II diabetes. (db/db) mice conversion, ↓p62. ↑SIRT1, ↓mTOR phosphorylated. Other metabolic and hepatic effects: ↓Circulating Glucose, ↓Insulin resistance, ↓Liver steatosis, ↓ALT and AST. Shao et al., 2018 Exenatide Fatty liver, diabetes. C57BL/6 mice High fat diet for Autophagy enhancement: ↑LC3 I to LC3 II 10 weeks and conversion, ↑Beclin, ↑Autophagosomes. treatment with ↑Mitophagy: ↑Parkin, ↑BNIP3L. Other streptozocin. metabolic and hepatic effects: ↓Circulating Glucose, ↓Liver steatosis, ↓ALT, ↓Oxidative stress. Cui et al., 2020 Chronic intermittent Metabolic syndrome: Sprague Dawley High fat diet and Autophagy enhancement: ↓LC3 I to LC3 II hypobaric hypoxia Fatty liver, Obesity, rats water conversion, ↓Beclin-1, ↓p62. ↓mTOR Hypertension, supplemented with phosphorylated, ↓ER stress (GRP78, CHOP). Hyperglycemia, fructose for Other metabolic and hepatic effects: Hypertriglyceridemia, 16 weeks. ↓Circulating Glucose, ↓Circulating Triglycerides, Insulin resistance. ↓Insulin resistance, ↓Liver steatosis, ↓ALT and AST. to verify whether quantification of lipolysosomes could be a develop therapies to improve the postoperative results of feasible and reproducible tool to assess the severity of NAFLD livers affected by obesity, MetS, NAFLD, or diabetes that are and its propensity to progress. The p62/SQSTM1 is essential subjected to surgery. for LC3B recruitment in LD in ethanol-induced lipophagy, As described in this review, autophagy is closely involved while p62/SQSTM1 knockdown triggers the accumulation of in signaling pathways underlying effects of obesity, MetS, and triglycerides and cholesterol. Recent reports suggest that serum obesity on the liver; and also is implicated as molecular p62/SQSTM1 levels could also become a potential biomarker in mechanisms to NAFLD and the extent of the damage caused the diagnosis of patients with steatosis and lobular inflammation by I/R as well as in surgical outcomes. These characteristics (Kuo et al., 2020). These may all become very valuable make autophagy regulation the basis of promising treatments non-invasive tools to evaluate liver injury in the immediate in patients suffering from the conditions aforementioned and postoperative period in patients subjected to liver resection or submitted to liver surgery. Unfortunately, whether hepatic transplantation. autophagy following warm or cold I/R protects or contributes to the damage is still unsolved since results are controversial. There are even controversies as to how the regulation of hepatic CONCLUSION autophagia occurs in conditions of obesity, MetS, NAFLD, or diabetes. This lack of understanding hampers their translation Due to the high prevalence of obesity, MetS, NAFLD, and from bench to bedside. diabetes, in the coming years, there may be a need to use Therefore, it is mandatory to increase the knowledge about liver grafts from donors with these metabolic diseases to autophagic molecular signaling in experimental or clinical reduce the waiting list for liver transplantation. In the same models of obesity, MetS, NAFLD, or diabetes subjected to way, the prevalence of such diseases causes an increasing resection or transplantation. In this last surgical situation, it is presence of such diseases in liver resections. Livers with important to clarify the mechanisms taking place in the recipient underlying pathological conditions possess higher sensitivity and donor. It should be bearing in mind that in clinical practice to I/R injury inherent to transplantation and resection and the most common scenario is patients combining NAFLD, are at high risk of morbidity or mortality in the immediate obesity, MetS, or diabetes, and for this reason, preclinical studies postoperative period. Therefore, there is a growing need to must use adequate experimental ischemia when evaluating the Frontiers in Cell and Developmental Biology | www.frontiersin.org 24 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome relevance of autophagy in the setting of I/R. This knowledge FUNDING is the premise for finding not only therapeutic strategies to prevent damage in patients with these metabolic diseases who This research was funded by the Ministerio de Ciencia, undergo surgery but also to find useful and non-invasive Innovación y Universidades (Project Grant RTI2018-095114- biomarkers to monitor the progression of liver damage in these B-I00) Madrid, Spain; European Union (Fondos FEDER, conditions. These advances would undoubtedly improve the “una manera de hacer Europa”); CERCA Program/Generalitat clinical prognosis of liver surgery in the coming years. de Catalunya; the Secretaria d’ Universitats I Recerca del Departament d’ Economia I Coneixement (Project Grant 2017_SGR_551) Barcelona, Spain, by the COST action Programs AUTHOR CONTRIBUTIONS CA17103 (DARTER), CA17112 (PRO-EURO-DILI-NET), CA17121 (COMULIS), and CA17126 (TUMIEE), and by the AÁ-M, CR-A, MM-C, and AC-C gathered the related literature, Consejo Nacional de Ciencia y Tecnología (CONACYT), Fondo prepared the figures, and drafted the manuscript. CP and Sectorial de Investigación para la Educación (Project grant AC-R participated in the design of the review and drafted the 257743), México. MM-C is the recipient of a fellowship from manuscript. All authors read and approved the final manuscript. FCT (Fundació Catalana de trasplantament), Spain. REFERENCES Bi, J., Yang, L., Wang, T., Zhang, J., Li, T., Ren, Y., et al. (2020). Irisin improves autophagy of aged hepatocytes via increasing telomerase activity in liver injury. Adeva-Andany, M. M., Carneiro-Freire, N., Seco-Filgueira, M., Fernandez- Oxid. Med. Cell. Longev. 2020:6946037. doi: 10.1155/2020/6946037 Fernandez, C., and Mourino-Bayolo, D. (2019). Mitochondrial beta-oxidation Biel, T. G., Lee, S., Flores-Toro, J. A., Dean, J. W., Go, K. L., Lee, M. H., et al. (2016). of saturated fatty acids in humans. Mitochondrion 46, 73–90. doi: 10.1016/j. Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mito.2018.02.009 mitofusin 2-dependent manner. Cell Death. Differ 23, 279–290. doi: 10.1038/ Adkins, Y., Schie, I. W., Fedor, D., Reddy, A., Nguyen, S., Zhou, P., et al. (2013). cdd.2015.96 A novel mouse model of nonalcoholic steatohepatitis with significant insulin Caraceni, P., Domenicali, M., Vendemiale, G., Grattagliano, I., Pertosa, A., Nardo, resistance. Lab. Investig. 93, 1313–1322. doi: 10.1038/labinvest.2013.123 B., et al. (2005). The reduced tolerance of rat fatty liver to ischemia reperfusion Alfany-Fernandez, I., Casillas-Ramirez, A., Bintanel-Morcillo, M., Brosnihan, is associated with mitochondrial oxidative injury. J. Surg. Res. 124, 160–168. K. B., Ferrario, C. M., Serafin, A., et al. (2009). Therapeutic targets in liver doi: 10.1016/j.jss.2004.10.007 transplantation: angiotensin II in nonsteatotic grafts and angiotensin-(1-7) in Carotti, S., Aquilano, K., Zalfa, F., Ruggiero, S., Valentini, F., Zingariello, steatotic grafts. Am. J. Transplant. 9, 439–451. doi: 10.1111/j.1600-6143.2008. M., et al. (2020). Lipophagy impairment is associated with disease 02521.x progression in NAFLD. Front. Physiol. 11:850. doi: 10.3389/fphys.2020. Alipourfard, I., Datukishvili, N., and Mikeladze, D. (2019). TNF-α downregulation 00850 modifies insulin receptor substrate 1 (IRS-1) in metabolic signaling of diabetic Carrasco-Chaumel, E., Roselló-Catafau, J., Bartrons, R., Franco-Gou, R., Xaus, C., insulin-resistant hepatocytes. Mediators Inflamm. 2019:3560819. doi: 10.1155/ Casillas, A., et al. (2005). Adenosine monophosphate-activated protein kinase 2019/3560819 and nitric oxide in rat steatotic liver transplantation. J. Hepatol. 43, 997–1006. Álvarez-Mercado, A. I., Negrete-Sánchez, E., Gulfo, J., Ávalos De León, doi: 10.1016/j.jhep.2005.05.021 C. G., Casillas-Ramírez, A., Cornide-Petronio, M. E., et al. (2019). EGF- Casillas-Ramírez, A., Alfany-Fernández, I., Massip-Salcedo, M., Juan, M. E., Planas, GH axis in rat steatotic and non-steatotic liver transplantation from brain- J. M., Serafín, A., et al. (2011). Retinol-binding protein 4 and peroxisome dead donors. Transplantation 103, 1349–1359. doi: 10.1097/TP.0000000000 proliferator-activated receptor-γ in steatotic liver transplantation. J. Pharmacol. 002636 Exp. Ther. 338, 143–153. doi: 10.1124/jpet.110.177691 Archuleta, T. L., Lemieux, A. M., Saengsirisuwan, V., Teachey, M. K., Lind-borg, Casillas-Ramírez, A., Amine-Zaouali, M., Massip-Salcedo, M., Padrissa- K. A., Kim, J. S., et al. (2009). Oxidant stress-induced loss of IRS-1 and IRS-2 Altés, S., Bintanel-Morcillo, M., Ramalho, F., et al. (2008). Inhibition of proteins in rat skeletal muscle: role of p38 MAPK. Free. Radic. Biol. Med. 47, angiotensin II action protects rat steatotic livers against ischemia-reperfusion 1486–1493. doi: 10.1016/j.freeradbiomed.2009.08.014 injury. Crit. Care Med. 36, 1256–1266. doi: 10.1097/CCM.0b013e318 Bai, G., Li, H., Ge, Y., Zhang, Q., Zhang, J., Chen, M., et al. (2018). Influence 16a023c of hydrogen-rich saline on hepatocyte autophagy during laparoscopic liver Chae, S., Choi, J., Lim, S., Choi, H. J., Park, J., Hong, S. H., et al. (2020). Stress ischaemia-reperfusion combined resection injury in miniature pigs. J. Vet. Res. burden related to postreperfusion syndrome may aggravate hyperglycemia with 62, 395–403. doi: 10.2478/jvetres-2018-0056 insulin resistance during living donor liver transplantation: a propensity score- Baldini, F., Portincasa, P., Grasselli, E., Damonte, G., Salis, A., Bonomo, M., matching analysis. PLoS One 15:e0243873. doi: 10.1371/journal.pone.0243873 et al. (2020). Aquaporin-9 is involved in the lipid-lowering activity of the Chang, A. L., Cortez, A. R., Bondoc, A., Schauer, D. P., Fitch, A., Shah, S. A., nutraceutical silybin on hepatocytes through modulation of autophagy and et al. (2016). Metabolic syndrome in liver transplantation: a preoperative lipid droplets composition. Biochim. Biophys. Acta - Mol. Cell Biol. Lipids and postoperative concern. Surgery 160, 1111–1117. doi: 10.1016/j.surg. 1865:158586. doi: 10.1016/j.bbalip.2019.158586 2016.06.015 Bechmann, L. P., Hannivoort, R. A., Gerken, G., Hotamisligil, G. S., Trauner, M., Chen, K., Li, J. J., Li, S. N., Feng, J., Liu, T., Wang, F., et al. (2017a). 15-Deoxy- and Canbay, A. (2012). The interaction of hepatic lipid and glucose metabolism 112,14-prostaglandin J2 alleviates hepatic ischemia-reperfusion injury in mice in liver diseases. J. Hepatol. 56, 952–964. doi: 10.1016/j.jhep.2011.08.025 via inducing antioxidant response and inhibiting apoptosis and autophagy. Acta Behrends, M., Martinez-Palli, G., Niemann, C. U., Cohen, S., Ramachandran, Pharmacol. Sin. 38, 672–687. doi: 10.1038/aps.2016.108 R., and Hirose, R. (2010). Acute hyperglycemia worsens hepatic Chen, K., Yuan, R., Zhang, Y., Geng, S., and Li, L. (2017b). Tollip deficiency ischemia/reperfusion injury in rats. J. Gastrointest. Surg. 14, 528–535. alters atherosclerosis and steatosis by disrupting lipophagy. J. Am. Heart Assoc. doi: 10.1007/s11605-009-1112-3 6:e004078. doi: 10.1161/JAHA.116.004078 Ben Mosbah, I., Alfany-Fernández, I., Martel, C., Zaouali, M. A., Bintanel-Morcillo, Chen, X., Chan, H., Zhangm, L., Liu, X., Hom, I. H. T., Zhang, X., et al. (2019a). The M., Rimola, A., et al. (2010). Endoplasmic reticulum stress inhibition protects phytochemical polydatin ameliorates non-alcoholic steatohepatitis by restoring steatotic and non-steatotic livers in partial hepatectomy under ischemia- lysosomal function and autophagic flux. J. Cell. Mol. Med. 23, 4290–4300. reperfusion. Cell Death Dis. 1, 1–12. doi: 10.1038/cddis.2010.29 doi: 10.1111/jcmm.14320 Frontiers in Cell and Developmental Biology | www.frontiersin.org 25 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome Chen, X., Wang, L., Deng, Y., Li, X., Li, G., Zhou, J., et al. (2019b). Inhibition Fernández, L., Carrasco-Chaumel, E., Serafín, A., Xaus, C., Grande, L., Rimola, of autophagy prolongs recipient survival through promoting CD8+ T cell A., et al. (2004). Is ischemic preconditioning a useful strategy in steatotic liver apoptosis in a rat liver transplantation model. Front. Immunol. 10:1356. doi: transplantation? Am. J. Transplant. 4, 888–899. doi: 10.1111/j.1600-6143.2004. 10.3389/fimmu.2019.01356 00447.x Cho, H. I., Seo, M. J., and Lee, S. M. (2017). 2-Methoxyestradiol protects against Forbes, S. J., and Newsome, P. N. (2016). Liver regeneration - mechanisms and ischemia/reperfusion injury in alcoholic fatty liver by enhancing sirtuin 1- models to clinical application. Nat. Rev. Gastroenterol. Hepatol. 13, 473–485. mediated autophagy. Biochem. Pharmacol. 131, 40–51. doi: 10.1016/j.bcp.2017. doi: 10.1038/nrgastro.2016.97 02.008 Fortunato, F., Burgers, H., Bergmann, F., Rieger, P., Buchler, M. W., Kroemer, Choi, J. W., Ohn, J. H., Jung, H. S., Park, Y. J., Jang, H. C., Chung, S. S., et al. (2018). G., et al. (2009). Impaired autolysosome formation correlates with Lamp- Carnitine induces autophagy and restores high-fat diet-induced mitochondrial 2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis. dysfunction. Metabolism 78, 43–51. doi: 10.1016/j.metabol.2017.09.005 Gastroenterology 137, 350–360. doi: 10.1053/j.gastro.2009.04.003 Chorny, A., Anderson, P., Gonzalez-Rey, E., and Delgado, M. (2008). Ghrelin Gadiparthi, C., Spatz, M., Greenberg, S., Iqbal, U., Kanna, S., Satapathy, protects against experimental sepsis by inhibiting high-mobility group box S. K., et al. (2020). NAFLD Epidemiology, Emerging Pharmacotherapy, Liver 1 release and by killing bacteria. J. Immunol. 180, 8369–8377. doi: 10.4049/ Transplantation Implications and the Trends in the United States. J. Clin. jimmunol.180 12.8369 Transl. Hepatol. 8, 215–221. doi: 10.14218/JCTH.2020.00014 Cornide-Petronio, M. E., Bujaldon, E., Mendes-Braz, M., Avalos de León, C. G., Gjorgjieva, M., Mithieux, G., and Rajas, F. (2019). Hepatic stress associated with Jiménez-Castro, M. B., Álvarez-Mercado, A. I., et al. (2017). The impact of pathologies characterized by disturbed glucose production. Cell Stress 3, 86–99. cortisol in steatotic and non-steatotic liver surgery. J. Cell. Mol. Med. 21, doi: 10.15698/cst2019.03.179 2344–2358. doi: 10.1111/jcmm.13156 Gong, L. L., Li, G. R., Zhang, W., Liu, H., Lv, Y. L., Han, F. F., et al. (2016). Cui, F., Hu, H. F., Guo, J., Sun, J., and Shi, M. (2020). The effect of autophagy on Akebia saponin D decreases hepatic steatosis through autophagy modulation. chronic intermittent hypobaric hypoxia ameliorating liver damage in metabolic J. Pharmacol. Exp. Ther. 359, 392–400. doi: 10.1124/jpet.116.236562 syndrome rats. Front. Physiol. 11:13. doi: 10.3389/fphys.2020.00013 Gong, L. L., Yang, S., Zhang, W., Han, F. F., Lv, Y. L., Wan, Z. R., et al. Cui, Z., Li, S., Liu, Z., Zhang, Y., and Zhang, H. (2018). Interferon regulatory (2018). Akebia saponin D alleviates hepatic steatosis through BNip3 induced factor 1 activates autophagy to aggravate hepatic ischemia-reperfusion injury mitophagy. J. Pharmacol. Sci. 136, 189–195. doi: 10.1016/j.jphs.2017.11.007 by increasing high mobility group box 1 release. Cell. Physiol. Biochem. 48, Gonzalez, C. D., Lee, M. S., Marchetti, P., Pietropaolo, M., Towns, R., Vaccaro, 328–338. doi: 10.1159/000491732 M. I., et al. (2011). The emerging role of autophagy in the pathophysiology of Degli Esposti, D., Sebagh, M., Pham, P., Reffas, M., Poüs, C., Brenner, C., et al. diabetes mellitus. Autophagy 7, 2–11. doi: 10.4161/auto.7.1.13044 (2011). Ischemic preconditioning induces autophagy and limits necrosis in González, H. D., Liu, Z. W., Cashman, S., and Fusai, G. K. (2010). Small for human recipients of fatty liver grafts, decreasing the incidence of rejection size syndrome following living donor and split liver transplantation. World J. episodes. Cell Death Dis. 2:e111. doi: 10.1038/cddis.2010.89 Gastrointest. Surg. 2, 389–394. doi: 10.4240/wjgs.v2.i12.389 Deng, J., Feng, J., Liu, T., Lu, X., Wang, W., Liu, N., et al. (2018). Beraprost González-Rodríguez, A., Mayoral, R., Agra, N., Valdecantos, M. P., Pardo, V., sodium preconditioning prevents inflammation, apoptosis, and autophagy Miquilena-Colina, M. E., et al. (2014). Impaired autophagic flux is associated during hepatic ischemia-reperfusion injury in mice via the P38 and JNK with increased endoplasmic reticulum stress during the development of pathways. Drug Des. Devel. Ther. 12, 4067–4082. doi: 10.2147/DDDT.S182292 NAFLD. Cell Death Dis. 5:e1179. doi: 10.1038/cddis.2014.162 du Toit, A., Hofmeyr, J. S., Gniadek, T. J., and Loos, B. (2018). Measuring Goto, T., Elbahrawy, A., Furuyama, K., Horiguchi, M., Hosokawa, S., Aoyama, Y., autophagosome flux. Autophagy 14, 1060–1071. doi: 10.1080/15548627.2018. et al. (2017). Liver-specific Prox1 inactivation causes hepatic injury and glucose 1469590 intolerance in mice. FEBS Lett. 591, 624–635. doi: 10.1002/1873-3468.12570 Durczynski, A., Strzelczyk, J., Wojciechowska-Durczynska, K., Borkowska, A., Gotoh, K., Lu, Z., Morita, M., Shibata, M., Koike, M., Waguri, S., et al. (2009). Hogendorf, P., Szymanski, D., et al. (2013). Major liver resection results in Participation of autophagy in the initiation of graft dysfunction after rat liver early exacerbation of insulin resistance, and may be a risk factor of developing transplantation. Autophagy 5, 351–360. doi: 10.4161/auto.5.3.7650 overt diabetes in the future. Surg. Today 43, 534–538. doi: 10.1007/s00595-012-0 Gracia-Sancho, J., García-Calderó, H., Hide, D., Marrone, G., Guixé-Muntet, S., 268-8 Peralta, C., et al. (2013). Simvastatin maintains function and viability of steatotic Dusabimana, T., Kim, S. R., Kim, H. J., Kim, H., and Park, S. W. (2019). Nobiletin rat livers procured for transplantation. J. Hepatol. 58, 1140–1146. doi: 10.1016/ ameliorates hepatic ischemia and reperfusion injury through the activation of j.jhep.2013.02.005 SIRT-1/FOXO3a-mediated autophagy and mitochondrial biogenesis. Exp. Mol. Gupta, N. A., Kolachala, V. L., Jiang, R., Abramowsky, C., Shenoi, A., Kosters, Med. 51, 1–16. doi: 10.1038/s12276-019-0245-z A., et al. (2014). Mitigation of autophagy ameliorates hepatocellular damage El Atrache, M. M., Abouljoud, M. S., Divine, G., Yoshida, A., Kim, D. Y., following ischemia-reperfusion injury in murine steatotic liver. Am. J. Kazimi, M. M., et al. (2012). Recurrence of non-alcoholic steatohepatitis and Physiol. Gastrointest. Liver Physiol. 307, G1088–G1099. doi: 10.1152/ajpgi.002 cryptogenic cirrhosis following orthotopic liver transplantation in the context 10.2014 of the metabolic syndrome. Clin. Transplant. 26, 505–512. doi: 10.1111/ctr. Han, S., Ko, J. S., Jin, S. M., Park, H. W., Kim, J. M., Joh, J. W., et al. (2014). 12014 Intraoperative hyperglycemia during liver resection: predictors and association Elias-Miró, M., Massip-Salcedo, M., Raila, J., Schweigert, F., Mendes-Braz, with the extent of hepatocytes injury. PLoS One 9:e0109120. doi: 10.1371/ M., Ramalho, F., et al. (2012). Retinol binding protein 4 and retinol in journal.pone.0109120 steatotic and nonsteatotic rat livers in the setting of partial hepatectomy He, Q., Mei, D., Sha, S., Fan, S., Wang, L., and Dong, M. (2016). ERK-dependent under ischemia/reperfusion. Liver Transpl. 18, 1198–1208. doi: 10.1002/lt. mTOR pathway is involved in berberine-induced autophagy in hepatic steatosis. 23489 J. Mol. Endocrinol. 57, 251–260. doi: 10.1530/JME-16-0139 Engeli, S., Schling, P., Gorzelniak, K., Boschmann, M., Janke, J., Ailhaud, G., et al. Homma, T., and Fujii, J. (2020). Emerging connections between oxidative stress, (2003). The adipose-tissue renin-angiotensin-aldosterone system: role in the defective proteolysis, and metabolic diseases. Free Radic. Res. 0, 1–16. doi: metabolic syndrome? Int. J. Biochem. Cell Biol. 35, 807–825. doi: 10.1016/s1357- 10.1080/10715762.2020.1734588 2725(02)00311-4 Houben, T., Oligschlaeger, Y., Hendrikx, T., Bitorina, A. V., Walenbergh, S. M. A., Esser, N., Legrand-Poels, S., Piette, J., Scheen, A. J., and Paquot, N. (2014). Van Gorp, P. J., et al. (2017). Cathepsin D regulates lipid metabolism in murine Inflammation as a link between obesity, metabolic syndrome and type 2 steatohepatitis. Sci. Rep. 7:3494. doi: 10.1038/s41598-017-03796-5 diabetes. Diabetes Res. Clin. Pract. 105, 141–150. doi: 10.1016/j.diabres.2014. Hsu, H. C., Liu, C. H., Tsai, Y. C., Li, S. J., Chen, C. Y., Chu, C. H., et al. (2016). 04.006 Time-dependent cellular response in the liver and heart in a dietary-induced Feng, J., Zhang, Q., Mo, W., Wu, L., Li, S., Li, J., et al. (2017). Salidroside obese mouse model: the potential role of ER stress and autophagy. Eur. J. Nutr. pretreatment attenuates apoptosis and autophagy during hepatic ischemia– 55, 2031–2043. doi: 10.1007/s00394-015-1017-8 reperfusion injury by inhibiting the mitogen-activated protein kinase pathway Huang, Q., Wang, T., Yang, L., and Wang, H. Y. (2017). Ginsenoside Rb2 in mice. Drug Des. Devel. Ther. 11, 1989–2006. doi: 10.2147/DDDT.S136792 alleviates hepatic lipid accumulation by restoring autophagy via induction of Frontiers in Cell and Developmental Biology | www.frontiersin.org 26 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome sirt1 and activation of AMPK. Int. J. Mol. Sci. 18, 1–15. doi: 10.3390/ijms18 autophagy (4th edition). Autophagy 17, 1–382. doi: 10.1080/15548627.2020. 051063 1797280 Inami, Y., Yamashina, S., Izumi, K., Ueno, T., Tanida, I., Ikejima, K., et al. Koga, H., Kaushik, S., and Cuervo, A. M. (2010). Altered lipid content inhibits (2011). Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagic vesicular fusion. FASEB J. 24, 3052–3065. doi: 10.1096/fj.09-144519 autophagosomal acidification and cathepsin expression. Biochem. Biophys. Res. Kong, D., Hua, X., Qin, T., Zhang, J., He, K., and Xia, Q. (2019). Inhibition of Commun. 412, 618–625. doi: 10.1016/j.bbrc.2011.08.012 glycogen synthase kinase 3ß protects liver against ischemia/reperfusion injury Ingaramo, P. I., Ronco, M. T., Francés, D. E. A., Monti, J. A., Pisani, G. B., by activating 50 adenosine monophosphate-activated protein kinase-mediated Ceballos, M. P., et al. (2011). Tumor necrosis factor alpha pathways develops autophagy. Hepatol. Res. 49, 462–472. doi: 10.1111/hepr.13287 liver apoptosis in type 1 diabetes mellitus. Mol. Immunol. 48, 1397–1407. doi: Kou, X., Zhu, J., Xie, X., Hao, M., and Zhao, Y. (2020). The protective effect of 10.1016/j.molimm.2011.03.015 glycyrrhizin on hepatic ischemia-reperfusion injury in rats and possible related Jeong Kim, H., Joe, Y., Kim, S. K., Park, S. U., Park, J., Chen, Y., et al. (2017). signal pathway. Iran. J. Basic Med. Sci. 23, 1232–1238. doi: 10.22038/ijbms.2020. Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin- 44101.10334 2 via the PERK-eIF2α-ATF4 pathway. Free Radic. Biol. Med. 110, 81–91. doi: Kramer, C. K., Zinman, B., and Retnakaran, R. (2013). Short-term intensive insulin 10.1016/j.freeradbiomed.2017.05.026 therapy in type 2 diabetesmellitus: a systematic review and meta-analysis. Ji, J., Wu, L., Feng, J., Mo, W., Wu, J., Yu, Q., et al. (2020). Cafestol preconditioning Lancet Diabetes Endocrinol. 1, 28–34. doi: 10.1016/S2213-8587(13)70006-8 attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury Kuo, N. C., Huang, S. Y., Yang, C. Y., Shen, H. H., and Lee, Y. M. (2020). by inhibiting ERK/PPARγ pathway. Int. Immunopharmacol. 84:106529. doi: Involvement of HO-1 and autophagy in the protective effect of magnolol in 10.1016/j.intimp.2020.106529 hepatic steatosis-induced NLRP3 inflammasome activation in vivo and in vitro. Jiang, T., Zhan, F., Rao, Z., Pan, X., Zhong, W., Sun, Y., et al. (2019). Combined Antioxidants 9, 1–19. doi: 10.3390/antiox9100924 ischemic and rapamycin preconditioning alleviated liver ischemia and Kurahashi, T., Hamashima, S., Shirato, T., Lee, J., Homma, T., Kang, E. S., et al. reperfusion injury by restoring autophagy in aged mice. Int. Immunopharmacol. (2015). An SOD1 deficiency enhances lipid droplet accumulation in the fasted 74:105711. doi: 10.1016/j.intimp.2019.105711 mouse liver by aborting lipophagy. Biochem. Biophys. Res. Commun. 467, Jiménez-Castro, M. B., Casillas-Ramírez, A., Mendes-Braz, M., Massip-Salcedo, 866–871. doi: 10.1016/j.bbrc.2015.10.052 M., Gracia-Sancho, J., Elias-Miró, M., et al. (2013). Adiponectin and resistin Lamark, T., Perander, M., Outzen, H., Kristiansen, K., Overvatn, A., Michaelsen, protect steatotic livers undergoing transplantation. J. Hepatol. 59, 1208–1214. E., et al. (2003). Interaction codes within the family of mammalian Phox and doi: 10.1016/j.jhep.2013.07.015 Bem1p domain-containing proteins. J. Biol. Chem. 278, 34568–34581. doi: 10. Jiménez-Castro, M. B., Elias-Miro, M., Mendes-Braz, M., Lemoine, A., Rimola, A., 1074/jbc.M303221200 Rodés, J., et al. (2012). Tauroursodeoxycholic acid affects PPARγ and TLR4 in Lee, D. H., Park, S. H., Huh, Y. H., Jung Kim, M., Seo, H. D., Ha, T. Y., et al. (2020). Steatotic liver transplantation. Am. J. Transplant. 12, 3257–3271. doi: 10.1111/ Iridoids of Valeriana fauriei contribute to alleviating hepatic steatosis in obese j.1600-6143.2012.04261.x mice by lipophagy. Biomed. Pharmacother. 125:109950. doi: 10.1016/j.biopha. Jiménez-Castro, M. B., Negrete-Sánchez, E., Casillas-Ramírez, A., Gulfo, J., 2020.109950 Álvarez-Mercado, A. I., Cornide-Petronio, M. E., et al. (2017). The effect of Lee, H. S., Daniels, B. H., Salas, E., Bollen, A. W., Debnath, J., and Margeta, M. cortisol in rat steatotic and non-steatotic liver transplantation from brain-dead (2012). Clinical utility of LC3 and p62 immunohistochemistry in diagnosis of donors. Clin. Sci. 131, 733–746. doi: 10.1042/CS20160676 drug-induced autophagic vacuolar myopathies: a case-control study. PLoS One Jin, Y., Tan, Y., Chen, L., Liu, Y., and Ren, Z. (2018). Reactive oxygen species 7:e36221. doi: 10.1371/journal.pone.0036221 induces lipid droplet accumulation in HepG2 cells by increasing perilipin 2 Lee, K., Haddad, A., Osme, A., Kim, C., Borzou, A., Ilchenko, S., et al. (2018). expression. Int. J. Mol. Sci. 19:3445. doi: 10.3390/ijms19113445 Hepatic mitochondrial defects in a nonalcoholic fatty liver disease mouse Jung, S. H., Lee, W., Park, S. H., Lee, K. Y., Choi, Y. J., Choi, S., et al. model are associated with increased degradation of oxidative phosphorylation (2020). Diclofenac impairs autophagic flux via oxidative stress and lysosomal subunits. Mol. Cell Proteomics 17, 2371–2386. doi: 10.1074/mcp.RA118.000961 dysfunction: implications for hepatotoxicity. Redox. Biol. 37:101751. doi: 10. Lee, S., Kim, S., Hwang, S., Cherrington, N. J., and Ryu, D. Y. (2017). Dysregulated 1016/j.redox.2020.101751 expression of proteins associated with ER stress, autophagy and apoptosis in Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., tissues from nonalcoholic fatty liver disease. Oncotarget 8, 63370–63381. doi: et al. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in 10.18632/oncotarget.18812 autophagosome membranes after processing. EMBO J. 19, 5720–5728. doi: Lee, S., Rivera-Vega, M., Alsayed, H. M., Boesch, C., and Libman, I. (2015). 10.1093/emboj/19.21.5720 Metabolic inflexibility and insulin resistance in obese adolescents with non- Kan, C., Liu, A., Fang, H., Dirsch, O., Dahmen, U., and Boettcher, M. (2017). alcoholic fatty liver disease. Pediatr. Diabetes. 16, 211–218. doi: 10.1111/pedi. Induction of autophagy reduces ischemia/reperfusion injury in steatotic rat 12141 livers. J. Surg. Res. 216, 207–218. doi: 10.1016/j.jss.2017.04.012 Lee, S. C., Kim, K. H., Kim, O. H., Lee, S. K., and Kim, S. J. (2016). Activation Kang, R. A., Han, S., Lee, K. W., Kim, G. S., Choi, S. J., Ko, J. S., et al. (2018). of autophagy by everolimus confers hepatoprotection against ischemia– Portland intensive insulin therapy during living donor liver transplantation: reperfusion injury. Am. J. Transplant. 16, 2042–2054. doi: 10.1111/ajt.13729 association with postreperfusion hyperglycemia and clinical outcomes. Sci. Rep. Lehmann, T. G., Wheeler, M. D., Froh, M., Schwabe, R. F., Bunzendahl, H., 8:16306. doi: 10.1038/s41598-018-34655-6 Samulski, R. J., et al. (2003). Effects of three superoxide dismutase genes Khader, A., Yang, W.-L., Godwin, A., Prince, J. M., Nicastro, J. M., Coppa, G. F., delivered with an adenovirus on graft function after transplantation of fatty et al. (2017). Sirtuin 1 stimulation attenuates ischemic liver injury and enhances livers in the rat. Transplantation 76, 28–37. doi: 10.1097/01.TP.0000065299. mitochondrial recovery and autophagy. Crit. Care Med. 44, 651–663. doi: 10. 29900.17 1097/CCM.0000000000001637 Li, H., Pan, Y., Wu, H., Yu, S., Wang, J., Zheng, J., et al. (2020). Inhibition Kim, B. W., Kwon, D. H., and Song, H. K. (2016). Structure biology of selective of excessive mitophagy by N-acetyl-L-tryptophan confers hepatoprotection autophagy receptors. BMB Rep. 49, 73–80. doi: 10.5483/BMBRep.2016.49.2.265 against Ischemia-Reperfusion injury in rats. PeerJ 2020, 1–18. doi: 10.7717/ Kim, K. H., Jeong, Y. T., Oh, H., Kim, S. H., Cho, J. M., Kim, Y. N., et al. (2013). peerj.8665 Autophagy deficiency leads to protection from obesity and insulin resistance by Li, J., Lin, W., and Zhuang, L. (2020). CD5L-induced activation of autophagy inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92. doi: 10.1038/nm.3014 is associated with hepatoprotection in ischemic reperfusion injury via the Kirisako, T., Ichimura, Y., Okada, H., Kabeya, Y., Mizushima, N., Yoshimori, T., CD36/ATG7 axis. Exp. Ther. Med. 19, 2588–2596. doi: 10.3892/etm.2020.8497 et al. (2000). The reversible modification regulates the membrane-binding state Li, J., Zhang, Q. H., Li, S., Dai, W., Feng, J., Wu, L., et al. (2017). The natural product of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting fucoidan ameliorates hepatic ischemia–reperfusion injury in mice. Biomed. pathway. J. Cell Biol. 151, 263–276. doi: 10.1083/jcb.151.2.263 Pharmacother. 94, 687–696. doi: 10.1016/j.biopha.2017.07.109 Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Li, M., Xu, M., Li, J., Chen, L., Xu, D., Tong, Y., et al. (2018). Alda-1 ameliorates et al. (2021). Guidelines for the use and interpretation of assays for monitoring liver ischemia-reperfusion injury by activating aldehyde dehydrogenase 2 and Frontiers in Cell and Developmental Biology | www.frontiersin.org 27 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome enhancing autophagy in mice. J. Immunol. Res. 2018:9807139. doi: 10.1155/ formation and trypsinogen activation in rodent models of acute pancreatitis. 2018/9807139 J. Clin. Invest. 119, 3340–3355. doi: 10.1172/JCI38674 Li, R., Xin, T., Li, D., Wang, C., Zhu, H., and Zhou, H. (2018). Therapeutic effect Massip-Salcedo, M., Casillas-Ramirez, A., Franco-Gou, R., Bartrons, R., Mosbah, of sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the I. B., Serafin, A., et al. (2006). Heat shock proteins and mitogen-activated ERK–CREB pathway and Bnip3-mediated mitophagy. Redox. Biol. 18, 229–243. protein kinases in steatotic livers undergoing ischemia-reperfusion: some doi: 10.1016/j.redox.2018.07.011 answers. Am. J. Pathol. 168, 1474–1485. doi: 10.2353/ajpath.2006.050645 Li, S., Takahara, T., Fujino, M., Fukuhara, Y., Sugiyama, T., Li, X. K., et al. (2017). Massip-Salcedo, M., Zaouali, M. A., Padrissa-Altés, S., Casillas-Ramirez, A., Rodés, Astaxanthin prevents ischemia-reperfusion injury of the steatotic liver in mice. J., Roselló-Catafau, J., et al. (2008). Activation of peroxisome proliferator- PLoS One 12:e0187810. doi: 10.1371/journal.pone.0187810 activated receptor-alpha inhibits the injurious effects of adiponectin in rat Li, S., Zhang, J., Wang, Z., Wang, T., Yu, Y., He, J., et al. (2016). MicroRNA- steatotic liver undergoing ischemia-reperfusion. Hepatology 47, 461–472. doi: 17 regulates autophagy to promote hepatic ischemia/reperfusion injury 10.1002/hep.21935 via suppression of signal transductions and activation of transcription-3 Matter, M. S., Decaens, T., Andersen, J. B., and Thorgeirsson, S. S. (2014). Targeting expression. Liver Transplant. 22, 1697–1709. doi: 10.1002/lt.24606 the mTOR pathway in hepatocellular carcinoma: current state and future Li, X., Gong, H., Yang, S., Yang, L., Fan, Y., and Zhou, Y. (2017). Pectic bee trends. J. Hepatol. 60, 855–865. doi: 10.1016/j.jhep.2013.11.031 pollen polysaccharide from Rosa rugosa alleviates diet-induced hepatic steatosis McCormack, L., Petrowsky, H., Jochum, W., Furrer, K., and Clavien, P. A. (2007). and insulin resistance via induction of AMPK/mTOR-mediated autophagy. Hepatic steatosis is a risk factor for postoperative complications after major Molecules 22:699. doi: 10.3390/molecules22050699 hepatectomy: a matched case-control study. Ann. Surg. 245, 923–930. doi: 10. Lin, Y., Sheng, M., Weng, Y., Xu, R., Lu, N., Du, H., et al. (2017). Berberine protects 1097/01.sla.0000251747.80025.b7 against ischemia/reperfusion injury after orthotopic liver transplantation via Mei, S., Ni, H. M., Manley, S., Bockkus, A., Kassel, K. M., Luyendyk, J. P., et al. activating Sirt1/FoxO3α induced autophagy. Biochem. Biophys. Res. Commun. (2011). Differential roles of unsaturated and saturated fatty acids on autophagy 483, 885–891. doi: 10.1016/j.bbrc.2017.01.028 and apoptosis in hepatocytes. J. Pharmacol. Exp. Ther. 339, 487–498. doi: 10. Lin, Y. C., Chang, P. F., Lin, H. F., Liu, K., Chang, M. H., and Ni, Y. H. (2016). 1124/jpet.111.184341 Variants in the autophagy-related gene IRGM confer susceptibility to non- Menikdiwela, K. R., Ramalingam, L., Rasha, F., Wang, S., Dufour, J. M., alcoholic fatty liver disease by modulating lipophagy. J. Hepatol. 65, 1209–1216. Kalupahana, N. S., et al. (2020). Autophagy in metabolic syndrome: breaking doi: 10.1016/j.jhep.2016.06.029 the wheel by targeting the renin–angiotensin system. Cell Death Dis. 11:87. Linecker, M., Limani, P., Kambakamba, P., Kron, P., Tschuor, C., Calo, N., et al. doi: 10.1038/s41419-020-2275-9 (2017). Omega-3 fatty acids protect fatty and lean mouse livers after major Micó-Carnero, M., Rojano-Alfonso, C., Álvarez-Mercado, A. I., Gracia-Sancho, hepatectomy. Ann. Surg. 266, 324–332. doi: 10.1097/SLA.0000000000001968 J., Casillas-Ramírez, A., and Peralta, C. (2021). Effects of gut metabolites and Ling, Q., Yu, X., Wang, T., Wang, S. G., Ye, Z. Q., and Liu, J. H. (2017). Roles of the microbiota in healthy and marginal livers submitted to surgery. Int. J. Mol. Sci. exogenous H2S-mediated SR a signaling pathway in renal ischemia/ reperfusion 22, 1–28. doi: 10.3390/ijms22010044 injury in regulating endoplasmic reticulum stress-induced autophagy in a rat Minor, T., Koetting, M., Koetting, M., Kaiser, G., Efferz, P., Lüer, B., et al. (2011). model. Cell Physiol. Biochem. 41, 2461–2474. doi: 10.1159/000475915 Hypothermic reconditioning by gaseous oxygen improves survival after liver Liu, A., Guo, E., Yang, J., Li, R., Yang, Y., Liu, S., et al. (2016). Ischemic transplantation in the pig. Am. J. Transplant. 11, 2627–2634. doi: 10.1111/j. preconditioning attenuates ischemia/reperfusion injury in rat steatotic liver: 1600-6143.2011.03731.x role of heme oxygenase-1-mediated autophagy. Oncotarget 7, 78372–78386. Miyagawa, K., Oe, S., Honma, Y., Izumi, H., Baba, R., and Harada, M. (2016). Lipid- doi: 10.18632/oncotarget.13281 induced endoplasmic reticulum stress impairs selective autophagy at the step of Liu, H., Dong, J., Song, S., Zhao, Y., Wang, J., Fu, Z., et al. (2019). Spermidine autophagosome-lysosome fusion in hepatocytes. Am. J. Pathol. 186, 1861–1873. ameliorates liver ischaemia-reperfusion injury through the regulation of doi: 10.1016/j.ajpath.2016.03.003 autophagy by the AMPK-mTOR-ULK1 signalling pathway. Biochem. Biophys. Miyamoto, S., and Heller, B. J. (2016). Drp1 and mitochondrial autophagy lend Res. Commun. 519, 227–233. doi: 10.1016/j.bbrc.2019.08.162 a helping hand in adaptation to pressure overload. Circulation 133:1225. doi: Liu, H. Y., Han, J., Cao, S. Y., Hong, T., Zhuo, D., Shi, J., et al. (2009). 10.1161/CIRCULATIONAHA.116.021796 Hepatic autophagy is suppressed in the presence of insulin resistance and Miyauchi, T., Uchida, Y., Kadono, K., Hirao, H., Kawasoe, J., Watanabe, T., hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy et al. (2019). Up-regulation of FOXO1 and reduced inflammation by β- genes by insulin. J. Biol. Chem. 284, 31484–31492. doi: 10.1074/jbc.M109. hydroxybutyric acid are essential diet restriction benefits against liver injury. 033936 Proc. Natl. Acad. Sci. U.S.A. 116, 13533–13542. doi: 10.1073/pnas.1820 Liu, P., Lin, H., Xu, Y., Zhou, F., Wang, J., Liu, J., et al. (2018). Frataxin-mediated 282116 PINK1-parkin-dependent mitophagy in hepatic steatosis: the protective effects Mizushima, N., Yoshimori, T., and Levine, B. (2010). Methods in mammalian of quercetin. Mol. Nutr. Food. Res. 62:e1800164. doi: 10.1002/mnfr.201800164 autophagy research. Cell 140, 313–326. doi: 10.1016/j.cell.2010.01.028 Liu, T., Han, Y., Lv, W., Qi, P., Liu, W., Cheng, Y., et al. (2019). GSK-3β mediates Nakamura, K., Kageyama, S., Ito, T., Hirao, H., Kadono, K., Aziz, A., et al. (2019). ischemia-reperfusion injury by regulating autophagy in DCD liver allografts. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. Int. J. Clin. Exp. Pathol. 12, 640–656. J. Clin. Invest. 129, 3420–3434. doi: 10.1172/JCI127550 Liu, Z., Ye, S., Zhong, X., Wang, W., Lai, C. H., Yang, W., et al. (2020). Pretreatment Nakamura, K., Kageyama, S., Yue, S., Huang, J., Fujii, T., Sosa, R. A., et al. with the ALDH2 activator Alda-1 protects rat livers from ischemia/reperfusion (2018). Heme oxygenase-1 regulates sirtuin-1 – autophagy pathway in liver injury by inducing autophagy. Mol. Med. Rep. 22, 2373–2385. doi: 10.3892/ transplantation: from mouse-to-human. Am. J. Transplant. 18, 1110–1121. doi: mmr.2020.11312 10.1111/ajt.14586.Heme Lopez-Neblina, F., Toledo, A. H., and Toledo-Pereyra, L. H. (2005). Molecular Nakao, Y. M., Miyawaki, T., Yasuno, S., Nakao, K., Tanaka, S., Ida, M., et al. biology of apoptosis in ischemia and reperfusion. J. Invest. Surg. 18, 335–350. (2012). Intra-abdominal fat area is a predictor for new onset of individual doi: 10.1080/08941930500328862 components of metabolic syndrome: MEtabolic syndRome and abdominaL Manna, P., Das, J., Ghosh, J., and Sil, P. C. (2010). Contribution of type 1 diabetes ObesiTy (MERLOT study). Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci. 88, 454–461. to rat liver dysfunction and cellular damage via activation of NOS, PARP, doi: 10.2183/pjab.88.454 IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: Ning, X. J., Yan, X., Wang, Y. F., Wang, R., Fan, X. L., Zhong, Z. B., et al. (2018). prophylactic role of arjunolic acid. Free Radic. Biol. Med. 48, 1465–1484. doi: Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying 10.1016/j.freeradbiomed.2010.02.025 decreased mitochondrial autophagy, increased apoptosis, impaired DNA Mao, Y., Zhang, S., Yu, F., Li, H., Guo, C., and Fan, X. (2015). Ghrelin attenuates damage repair and altered cell cycle distribution. Mol. Med. Rep. 18, 5663–5668. liver fibrosis through regulation of TGF-β1 expression and autophagy. Int. J. doi: 10.3892/mmr.2018.9606 Mol. Sci. 16, 21911–21930. doi: 10.3390/ijms160921911 Oberkofler, H., Pfeifenberger, A., Soyal, S., Felder, T., Hahne, P., Miller, K., et al. Mareninova, O. A., Hermann, K., French, S. W., O’Konski, M. S., Pandol, S. J., (2010). Aberrant hepatic TRIB3 gene expression in insulin-resistant obese Webster, P., et al. (2009). Impaired autophagic flux mediates acinar cell vacuole humans. Diabetologia 53, 1971–1975. doi: 10.1007/s00125-010-1772-2 Frontiers in Cell and Developmental Biology | www.frontiersin.org 28 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome Ogihara, T., Asano, T., Ando, K., Chiba, Y., Sakoda, H., Anai, M., et al. (2002). Settembre, C., De Cegli, R., Mansueto, G., Saha, P. K., Vetrini, F., Visvikis, O., et al. Angiotensin II-induced insulin resistance is associated with enhanced insulin (2013). TFEB controls cellular lipid metabolism through a starvation-induced signaling. Hypertension 40, 872–879. doi: 10.1161/01.hyp.0000040262.48405.a8 autoregulatory loop. Nat. Cell Biol. 15, 647–658. doi: 10.1038/ncb2718 Panisello-Roselló, A., Verde, E., Lopez, A., Flores, M., Folch-Puy, E., Rolo, A., Shaker, M. E., Trawick, B. N., and Mehal, W. Z. (2016). The novel TLR9 antagonist et al. (2018). Cytoprotective mechanisms in fatty liver preservation against cold COV08-0064 protects from ischemia/reperfusion injury in non-steatotic and ischemia injury: a comparison between IGL-1 and HTK. Int. J. Mol. Sci. 19:348. steatotic mice livers. Biochem. Pharmacol. 112, 90–101. doi: 10.1016/j.bcp.2016. doi: 10.3390/ijms19020348 05.003 Panisello-Roselló, A., Verde, E., Zaouali, M. A., Flores, M., Alva, N., Lopez, A., Shao, N., Yu, X. Y., Ma, X. F., Lin, W. J., Hao, M., and Kuang, H. Y. (2018). et al. (2017). The relevance of the UPS in fatty liver graft preservation: a new Exenatide delays the progression of nonalcoholic fatty liver disease in C57BL/6 approach for IGL-1 and HTK solutions. Int. J. Mol. Sci. 18, 1–10. doi: 10.3390/ Mice, which may involve inhibition of the NLRP3 inflammasome through the ijms18112287 mitophagy pathway. Gastroenterol. Res. Pract. 2018:1864307. doi: 10.1155/2018/ Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J. A., Outzen, H., et al. 1864307 (2007). p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of Simmons, R. K., Alberti, K. G., Gale, E. A., Colagiuri, S., Tuomilehto, J., Qiao, Q., ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131– et al. (2010). The metabolic syndrome: useful concept or clinical tool? Report 24145. doi: 10.1074/jbc.M702824200 of a WHO expert consultation. Diabetologia 53, 600–605. doi: 10.1007/s00125- Pantazi, E., Zaouali, M. A., Bejaoui, M., Folch-Puy, E., Abdennebi, H. B., Varela, 009-1620-4 A. T., et al. (2015). Sirtuin 1 in rat orthotopic liver transplantation: an IGL- Singh, R., and Cuervo, A. M. (2012). Lipophagy: connecting autophagy and lipid 1 preservation solution approach. World J. Gastroenterol. 21, 1765–1774. doi: metabolism. Int. J. Cell Biol. 2012:282041. doi: 10.1155/2012/282041 10.3748/wjg.v21.i6.1765 Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., et al. (2009). Parafati, M., Lascala, A., Morittu, V. M., Trimboli, F., Rizzuto, A., Brunelli, E., et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135. doi: 10.1038/ (2015). Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease nature07976 via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic Sinha, R. A., Farah, B. L., Singh, B. K., Siddique, M. M., Li, Y., Wu, Y., et al. (2014). syndrome. J. Nutr. Biochem. 26, 938–948. doi: 10.1016/j.jnutbio.2015.03.008 Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal Pereira, S., Shah, A., George Fantus, I., Joseph, J. W., and Giacca, A. (2015). Effect pathway in mice. Hepatology 59, 1366–1380. doi: 10.1002/hep.26667 of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid Stayrook, K. R., Bramlett, K. S., Savkur, R. S., Ficorilli, J., Cook, T., Christe, elevation. J. Endocrinol. 225, 1–7. doi: 10.1530/JOE-14-0676 M. E., et al. (2005). Regulation of carbohydrate metabolism by the farnesoid Putnam, K., Shoemaker, R., Yiannikouris, F., and Cassis, L. A. (2012). The X receptor. Endocrinology 146, 984–991. renin-angiotensin system: a target of and contributor to dyslipidemias, altered Su, Z., Nie, Y., Huang, X., Zhu, Y., Feng, B., Tang, L., et al. (2019). Mitophagy glucose homeostasis, and hypertension of the metabolic syndrome. Am. J. in hepatic insulin resistance: therapeutic potential and concerns. Front. Physiol. Heart Circ. Physiol. 302, H1219–H1230. doi: 10.1152/ajpheart.00796 Pharmacol. 10:1193. doi: 10.3389/fphar.2019.01193 .2011 Sun, X.-L., Zhang, Y.-L., Xi, S.-M., Ma, L.-J., and Li, S.-P. (2019). MiR-330-3p Quan, W., Hur, K. Y., Lim, Y., Oh, S. H., Lee, J. C., Kim, K. H., et al. (2012). suppresses phosphoglycerate mutase family member 5 -inducted mitophagy to Autophagy deficiency in beta cells leads to compromised unfolded protein alleviate hepatic ischemia-reperfusion injury. J. Cell. Biochem. 120, 4255–4267. response and progression from obesity to diabetes in mice. Diabetologia 55, doi: 10.1002/jcb.27711 392–403. doi: 10.1007/s00125-011-2350-y Tan, R., Tian, H., Yang, B., Zhang, B., Dai, C., Han, Z., et al. (2018). Autophagy Ricca, L., Lemoine, A., Cauchy, F., Hamelin, J., Sebagh, M., Esposti, D. D., and Akt in the protective effect of erythropoietin helix B surface peptide against et al. (2015). Ischemic postconditioning of the liver graft in adult hepatic ischaemia/reperfusion injury in mice. Sci. Rep. 8, 1–9. doi: 10.1038/ liver transplantation. Transplantation 99, 1633–1643. doi: 10.1097/TP. s41598-018-33028-3 0000000000000685 Tanaka, S., Hikita, H., Tatsumi, T., Sakamori, R., Nozaki, Y., Sakane, S., et al. Ricchi, M., Odoardi, M. R., Carulli, L., Anzivino, C., Ballestri, S., Pinetti, A., et al. (2016). Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and (2009). Differential effect of oleic and palmitic acid on lipid accumulation lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology 64, and apoptosis in cultured hepatocytes. J. Gastroenterol. Hepatol. 24, 830–840. 1994–2014. doi: 10.1002/hep.28820 doi: 10.1111/j.1440-1746.2008.05733.x Tang, B., Bao, N., He, G., and Wang, J. (2019). Long noncoding RNA Ruan, Z., Liang, M., Deng, X., Lai, M., Shang, L., and Su, X. (2019). Exogenous HOTAIR regulates autophagy via the miR-20b-5p/ATG7 axis in hepatic hydrogen sulfide protects fatty liver against ischemia-reperfusion injury by ischemia/reperfusion injury. Gene 686, 56–62. doi: 10.1016/j.gene.2018.10.059 regulating endoplasmic reticulum stress-induced autophagy in macrophage Tashiro, H., Kuroda, S., Mikuriya, Y., and Ohdan, H. (2014). Ischemia–reperfusion through mediating the class A scavenger receptor pathway in rats. Cell Biol. Int. injury in patients with fatty liver and the clinical impact of steatotic liver on 44, 306–316. doi: 10.1002/cbin.11234 hepatic surgery. Surg. Today 44, 1611–1625. doi: 10.1007/s00595-013-0736-9 Samala, N., Tersey, S. A., Chalasani, N., Anderson, R. M., and Mirmira, R. G. Toledo, M., Batista-Gonzalez, A., Merheb, E., Aoun, M. L., Tarabra, E., Feng, (2017). Molecular mechanisms of nonalcoholic fatty liver disease: potential role D., et al. (2018). Autophagy regulates the liver clock and glucose metabolism for 12-lipoxygenase. J. Diabetes Complications 31, 1630–1637. doi: 10.1016/j. by degrading CRY1. Cell Metab. 28, 268.e4–281.e4. doi: 10.1016/j.cmet.2018.0 jdiacomp.2017.07.014 5.023 Sato, S., and Furuya, N. (2017). Induction of PINK1/Parkin-mediated mitophagy. Uchiyama, Y. (2001). Autophagic cell death and its execution by lysosomal Methods Mol. Biol. 1759, 9–17. doi: 10.1007/7651_2017_7 cathepsins. Arch. Histol. Cytol. 64, 233–246. doi: 10.1679/aohc.64.233 Schleinitz, D., Böttcher, Y., Blüher, M., and Kovacs, P. (2014). The genetics of fat Vanhorebeek, I., Gunst, J., Derde, S., Derese, I., Boussemaere, M., Güiza, F., distribution. Diabetologia 57, 1276–1286. doi: 10.1007/s00125-014-3214-z et al. (2011). Insufficient activation of autophagy allows cellular damage to Schott, M. B., Weller, S. G., Schulze, R. J., Krueger, E. W., Drizyte-Miller, K., accumulate in critically ill patients. J. Clin. Endocrinol. Metab. 96, 633–645. Casey, C. A., et al. (2019). Lipid droplet size directs lipolysis and lipophagy doi: 10.1210/jc.2010-2563 catabolism in hepatocytes. J. Cell Biol. 218, 3320–3335. doi: 10.1083/jcb.201 Vida Perez, L., Montero Alvarez, J. L., Poyato Gonzalez, A., Briceño Delgado, J., 803153 Costan Rodero, G., Fraga Rivas, E., et al. (2016). Prevalence and predictors Schulze, R. J., and McNiven, M. A. (2014). A well-oiled machine: DNM2/dynamin of metabolic syndrome after liver transplantation. Transplant. Proc. 48, 2519– 2 helps keep hepatocyte lipophagy running smoothly. Autophagy 10, 388–389. 2524. doi: 10.1016/j.transproceed.2016.08.029 doi: 10.4161/auto.27486 Wan, X., Xu, C., Yu, C., and Li, Y. (2016). Role of NLRP3 Inflammasome in the Selzner, M., Rüdiger, H. A., Sindram, D., Madden, J., and Clavien, P. A. Progression of NAFLD to NASH. Can. J. Gastroenterol. Hepatol. 2016:6489012. (2000). Mechanisms of ischemic injury are different in the steatotic doi: 10.1155/2016/6489012 and normal rat liver. Hepatology. 32, 1280–1288. doi: 10.1053/jhep.2000. Wang, C., Niederstrasser, H., Douglas, P. M., Lin, R., Jaramillo, J., Li, Y., et al. 20528 (2017). Small-molecule TFEB pathway agonists that ameliorate metabolic Frontiers in Cell and Developmental Biology | www.frontiersin.org 29 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome syndrome in mice and extend C. elegans lifespan. Nat. Commun. 8:2270. doi: Xue, Z., Zhang, Y., Liu, Y., Zhang, C., Shen, X., Gao, F., et al. (2020). PACAP 10.1038/s41467-017-02332-3 neuropeptide promotes hepatocellular protection via CREB-KLF4 dependent Wang, H., Sun, R. Q., Zeng, X. Y., Zhou, X., Li, S., Jo, E., et al. (2015). Restoration autophagy in mouse liver ischemia reperfusion injury. Theranostics 10, 4453– of autophagy alleviates hepatic ER stress and impaired insulin signalling 4465. doi: 10.7150/thno.42354 transduction in high fructose-fed male mice. Endocrinology 156, 169–181. doi: Yan, B., Luo, J., Kaltenmeier, C., Du, Q., Stolz, D. B., Loughran, P., et al. 10.1210/en.2014-1454 (2020). Interferon Regulatory Factor-1 (IRF1) activates autophagy to promote Wang, H. J., Park, J. Y., Kwon, O., Choe, E. Y., Kim, C. H., Hur, K. Y., liver ischemia/reperfusion injury by inhibiting β-catenin in mice. PLoS One et al. (2015). Chronic HMGCR/HMG-CoA reductase inhibitor treatment 15:e0239119. doi: 10.1371/journal.pone.0239119 contributes to dysglycemia by upregulating hepatic gluconeogenesis through Yan, H., Gao, Y., and Zhang, Y. (2017). Inhibition of JNK suppresses autophagy induction. Autophagy 11, 2089–2101. doi: 10.1080/15548627.2015. autophagy and attenuates insulin resistance in a rat model of nonalcoholic 1091139 fatty liver disease. Mol. Med. Rep. 15, 180–186. doi: 10.3892/mmr.201 Wang, H., Zhang, Q., Wen, Q., Zheng, Y., Lazarovici, P., Jiang, H., et al. (2012). 6.5966 Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of Yang, J. H., Chen, Q., Tian, S. Y., Song, S. H., Liu, F., Wang, Q. X., et al. (2015). PI3k/Akt signaling pathway. Cell. Signal. 24, 17–24. doi: 10.1016/j.cellsig.2011. The role of 1,25-dyhydroxyvitamin D3 in mouse liver ischemia reperfusion 08.010 injury: regulation of autophagy through activation of mek/erk signaling and Wang, J., Deng, M., Wu, H., Wang, M., Gong, J., Bai, H., et al. pten/pi3k/akt/mtorc1 signaling. Am. J. Transl. Res. 7, 2630–2645. (2020). Suberoylanilide hydroxamic acid alleviates orthotopic liver Yang, L., Li, P., Fu, S., Calay, E. S., and Hotamisligil, G. S. (2010). Defective hepatic transplantation-induced hepatic ischemia-reperfusion injury by regulating the autophagy in obesity promotes ER stress and causes insulin resistance. Cell AKT/GSK3ß/NF-?B and AKT/mTOR pathways in rat Kupffer cells. Int. J. Mol. Metab. 11, 467–478. doi: 10.1016/j.cmet.2010.04.005 Med. 45, 1875–1887. doi: 10.3892/ijmm.2020.4551 Yasuda-Yamahara, M., Kume, S., Yamahara, K., Nakazawa, J., Chin-Kanasaki, M., Wang, Q., Wei, S., Zhou, S., Qiu, J., Shi, C., Liu, R., et al. (2020). Hyperglycemia Araki, H., et al. (2015). Lamp-2 deficiency prevents high-fat diet-induced obese aggravates acute liver injury by promoting liver-resident macrophage NLRP3 diabetes via enhancing energy expenditure. Biochem. Biophys. Res. Commun. inflammasome activation via the inhibition of AMPK/mTOR-mediated 465, 249–255. doi: 10.1016/j.bbrc.2015.08.010 autophagy induction. Immunol. Cell Biol. 98, 54–66. doi: 10.1111/imcb.12297 Yu, Q., Wu, L., Liu, T., Li, S., Feng, J., Mao, Y., et al. (2019). Protective effects of Wang, R. R., Shen, Z. Y., Yang, L., Yin, M. L., Zheng, W. P., Wu, B., et al. levo-tetrahydropalmatine on hepatic ischemia/reperfusion injury are mediated (2017). Protective effects of heme oxygenase-1-transduced bone marrow- by inhibition of the ERK/NF-κB pathway. Int. Immunopharmacol. 70, 435–445. derived mesenchymal stem cells on reduced-size liver transplantation: role of doi: 10.1016/j.intimp.2019.02.024 autophagy regulated by the ERK/mTOR signaling pathway. Int. J. Mol. Med. 40, Yu, X., Huang, S., Deng, Q., Tang, Y., Yao, P., Tang, H., et al. (2019). Linseed 1537–1548. doi: 10.3892/ijmm.2017.3121 oil improves hepatic insulin resistance in obese mice through modulating Wang, W., Wu, L., Li, J., Ji, J., Chen, K., Yu, Q., et al. (2019). Alleviation of mitochondrial quality control. J. Funct. Foods 53, 166–175. doi: 10.1016/j.jff. hepatic ischemia reperfusion injury by oleanolic acid pretreating via reducing 2018.12.016 HMGB1 release and inhibiting apoptosis and autophagy. Mediators Inflamm. Yu, Y., Li, S., Wang, Z., He, J., Ding, Y., Zhang, H., et al. (2017). Interferon 2019:3240713. doi: 10.1155/2019/3240713 regulatory factor-1 activates autophagy to aggravate hepatic ischemia- Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., et al. (2018). reperfusion injury via the P38/P62 pathway in mice. Sci. Rep. 7:43684. doi: Defective lysosomal clearance of autophagosomes and its clinical implications 10.1038/srep43684 in nonalcoholic steatohepatitis. FASEB J. 32, 37–51. doi: 10.1096/fj.201601393R Zaouali, M. A., Bardag-Gorce, F., Carbonell, T., Oliva, J., Pantazi, E., Bejaoui, M., Wang, Z., Hou, L., Huang, L., Guo, J., and Zhou, X. (2017). Exenatide improves et al. (2013a). Proteasome inhibitors protect the steatotic and non-steatotic liver liver mitochondrial dysfunction and insulin resistance by reducing oxidative graft against cold ischemia reperfusion injury. Exp. Mol. Pathol. 94, 352–359. stress in high fat diet-induced obese mice. Biochem. Biophys. Res. Commun. 486, doi: 10.1016/j.yexmp.2012.12.005 116–123. doi: 10.1016/j.bbrc.2017.03.010 Zaouali, M. A., Boncompagni, E., Reiter, R. J., Bejaoui, M., Freitas, I., Pantazi, Williamson, R. M., Price, J. F., Glancy, S., Perry, E., Nee, L. D., Hayes, P. C., et al. E., et al. (2013b). AMPK involvement in endoplasmic reticulum stress (2011). Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty and autophagy modulation after fatty liver graft preservation: a role for liver disease in people with type 2 diabetes: the edinburgh type 2 diabetes study. melatonin and trimetazidine cocktail. J. Pineal Res. 55, 65–78. doi: 10.1111/jpi. Diabetes Care 34, 1139–1144. doi: 10.2337/dc10-2229 12051 Wu, L., Zhang, Q., Dai, W., Li, S., Feng, J., Li, J., et al. (2017). Quercetin Zaouali, M. A., Panisello, A., Lopez, A., Folch, E., Castro-Benítez, C., Adam, Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis R., et al. (2017). Cross-talk between sirtuin 1 and high-mobility box 1 in and Autophagy by Inhibiting ERK/NF-κ B pathway. Gastroenterol. Res. Pract. steatotic liver graft preservation. Transplant. Proc. 49, 765–769. doi: 10.1016/ 2017:9724217. doi: 10.1155/2017/9724217 j.transproceed.2017.01.071 Xiang, S., Chen, K., Xu, L., Wang, T., and Guo, C. (2020). Bergenin exerts Zeng, X., Wang, S., Li, S., Yang, Y., Fang, Z., Huang, H., et al. (2019). hepatoprotective effects by inhibiting the release of inflammatory factors, Hypothermic oxygenated machine perfusion alleviates liver injury in donation apoptosis and autophagy via the PPAR-γ pathway. Drug Des. Devel. Ther. 14, after circulatory death through activating autophagy in mice. Artif. Organs 43, 129–143. doi: 10.2147/DDDT.S229063 E320–E332. doi: 10.1111/aor.13525 Xiong, J., Wang, K., He, J., Zhang, G., Zhang, D., and Chen, F. (2016). Zhang, N., Sheng, M., Wu, M., Zhang, X., Ding, Y., Lin, Y., et al. (2019). Berberine TFE3 alleviates hepatic steatosis through autophagy-induced lipophagy and protects steatotic donor undergoing liver transplantation via inhibiting PGC1α-mediated fatty acid β-oxidation. Int. J. Mol. Sci. 17:387. doi: 10.3390/ endoplasmic reticulum stress-mediated reticulophagy. Exp. Biol. Med. 244, ijms17030387 1695–1704. doi: 10.1177/1535370219878651 Xu, D., Chen, L., Chen, X., Wen, Y., Yu, C., Yao, J., et al. (2017). The Zhang, X., Han, J., Man, K., Li, X., Du, J., Chu, E. S., et al. (2016). CXC chemokine triterpenoid CDDO-imidazolide ameliorates mouse liver ischemia-reperfusion receptor 3 promotes steatohepatitis in mice through mediating inflammatory injury through activating the Nrf2/HO-1 pathway enhanced autophagy. Cell cytokines, macrophages and autophagy. J. Hepatol. 64, 160–170. doi: 10.1016/j. Death Dis. 8:e2983. doi: 10.1038/cddis.2017.386 jhep.2015.09.005 Xu, S., Niu, P., Chen, K., Xia, Y., Yu, Q., Liu, N., et al. (2017). The liver protection Zhang, Z., Yao, Z., Chen, Y., Qian, L., Jiang, S., Zhou, J., et al. (2018). Lipophagy and of propylene glycol alginate sodium sulfate preconditioning against ischemia liver disease: new perspectives to better understanding and therapy. Biomed. reperfusion injury: focusing MAPK pathway activity. Sci. Rep. 7, 1–12. doi: Pharmacother. 97, 339–348. doi: 10.1016/j.biopha.2017.07.168 10.1038/s41598-017-15521-3 Zhao, Q., Guo, Z., Deng, W., Fu, S., Zhang, C., Chen, M., et al. (2016). Calpain Xu, Y., Tang, Y., Lu, J., Zhang, W., Zhu, Y., Zhang, S., et al. (2020). PINK1-mediated 2-mediated autophagy defect increases susceptibility of fatty livers to ischemia- mitophagy protects against hepatic ischemia/reperfusion injury by restraining reperfusion injury. Cell Death Dis. 7:e2186. doi: 10.1038/cddis.2016.66 NLRP3 inflammasome activation. Free Radic. Biol. Med. 160, 871–886. doi: Zhou, H., Du, W., Li, Y., Shi, C., Hu, N., Ma, S., et al. (2018). Effects of 10.1016/j.freeradbiomed.2020.09.015 melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, Frontiers in Cell and Developmental Biology | www.frontiersin.org 30 June 2021 | Volume 9 | Article 670273 Álvarez-Mercado et al. Autophagy in Liver Surgery and Metabolic Syndrome mitochondrial fission, and mitophagy. J. Pineal. Res. 64:1. doi: 10.1111/jpi. Conflict of Interest: The authors declare that the research was conducted in the 12450 absence of any commercial or financial relationships that could be construed as a Zhu, J., Yao, K., Wang, Q., Guo, J., Shi, H., Mam, L., et al. (2016). potential conflict of interest. Ischemic postconditioning-regulated miR-499 protects the rat heart against ischemia/reperfusion injury by inhibiting apoptosis through Copyright © 2021 Álvarez-Mercado, Rojano-Alfonso, Micó-Carnero, Caballeria- PDCD4. Cell Physiol. Biochem. 39, 2364–2380. doi: 10.1159/000 Casals, Peralta and Casillas-Ramírez. This is an open-access article distributed 452506 under the terms of the Creative Commons Attribution License (CC BY). The use, Zhu, S., Wu, Y., Ye, X., Ma, L., Qi, J., Yu, D., et al. (2016). FGF21 distribution or reproduction in other forums is permitted, provided the original ameliorates nonalcoholic fatty liver disease by inducing autophagy. author(s) and the copyright owner(s) are credited and that the original publication Mol. Cell. Biochem. 420, 107–119. doi: 10.1007/s11010-016- in this journal is cited, in accordance with accepted academic practice. No use, 2774-2 distribution or reproduction is permitted which does not comply with these terms. Frontiers in Cell and Developmental Biology | www.frontiersin.org 31 June 2021 | Volume 9 | Article 670273