Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease
Zarei, Mohammad (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Barroso, Emma (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Palomer, Xavier (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Dai, Jianli (University of the Chinese Academy of Sciences. Institute for Nutritional Sciences. Key Laboratory of Nutrition and Metabolism)
Rada, Patricia (Instituto de Salud Carlos III. Centro de Investigación Biomédica en Red)
Quesada-López, Tania (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Escolà-Gil, Joan Carles (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Cedó, Lídia (Institut d'Investigació Biomèdica Sant Pau)
Zali, Mohammad Reza (Shahid Beheshti University of Medical Sciences. Research Institute for Gastroenterology and Liver Diseases)
Molaei, Mahsa (Shahid Beheshti University of Medical Sciences. Research Institute for Gastroenterology and Liver Diseases)
Dabiri, Reza (Semnan University of Medical Sciences. lnternal Medicine Department)
Vázquez, Santiago (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Pujol Bech, Eugenia (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Valverde, Ángela M. (Instituto de Investigaciones Biomédicas "Alberto Sols")
Villarroya, Francesc (Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular)
Liu, Yong (Wuhan University. Institute for Advanced Studies)
Wahli, Walter (Nanyang Technological University. Lee Kong Chian School of Medicine)
Vázquez-Carrera, Manuel (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Universitat Autònoma de Barcelona

Data:	2018
Resum:	The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Studies were conducted in wild-type and Pparβ/δ -null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. Increased VLDLR levels were observed in liver of Pparβ/δ -null mice and in Pparβ/δ -knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21 -null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects. Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development.
Ajuts:	Ministerio de Economía y Competitividad SAF2015-65267-R Ministerio de Economía y Competitividad SAF2015-64146-R Ministerio de Economía y Competitividad SAF2014-55725
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	VLDLR ; PPAR ; FGF21 ; ATF4 ; ER stress ; ATF4, activating transcription factor 4 ; Chop, C/EBP homologous protein ; Eif2α, eukaryotic translation initiation factor 2α ; FGF21, fibroblast growth factor 21 ; HFD, high-fat diet ; HRI, heme-regulated eIF2α kinase ; NAFLD, non-alcoholic fatty liver disease ; PPAR, peroxisome proliferator-activated receptor
Publicat a:	Molecular metabolism, Vol. 8 (Feb. 2018) , p. 117-131, ISSN 2212-8778

DOI: 10.1016/j.molmet.2017.12.008
PMID: 29289645

15 p, 4.6 MB

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