Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System
Moure, Ricardo (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Domingo, Pere (Domingo Pedrol) (Institut d'Investigació Biomèdica Sant Pau)
Villarroya, Joan (Institut d'Investigació Biomèdica Sant Pau)
Gasa, Laura (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Gallego-Escuredo, José M. (Institut de Recerca Biomèdica (IRB) de Lleida)
Quesada-López, Tania (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Morón-Ros, Samantha (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Maroto, Alberto F. (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Mateo, Gracia M. (Institut d'Investigació Biomèdica Sant Pau)
Domingo, Joan C. (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Villarroya, Francesc (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Giralt, Marta (Universitat de Barcelona. Institut de Biomedicina (IBUB))
Universitat Autònoma de Barcelona

Date:	2018
Abstract:	Following antiretroviral therapy, HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor 21 (FGF21). In contrast, the expression of the FGF21-obligatory coreceptor β-Klotho (KLB) is reduced in target tissues. This situation is comparable to the FGF21 resistance status observed in obesity and type 2 diabetes. Here, we performed the first systematic study of the effects of distinct members of different antiretroviral drug classes on the FGF21/KLB system in human hepatic, adipose, and skeletal muscle cells. Most protease inhibitors and the nonnucleoside reverse transcriptase inhibitor efavirenz induced FGF21 gene expression. Neither nucleoside reverse transcriptase inhibitors nor the viral entry inhibitor maraviroc had any effect. Among the integrase inhibitors, elvitegravir significantly induced FGF21 expression, whereas raltegravir had minor effects only in adipose cells. In human hepatocytes and adipocytes, known target cells of FGF21 action, efavirenz, elvitegravir, and the lopinavir-ritonavir combination exerted inhibitory effects on KLB gene expression. Drug treatments that elicited FGF21 induction/KLB repression were those found to induce endoplasmic reticulum (ER) stress and oxidative stress. Notably, the pharmacological agents thapsigargin and tunicamycin, which induce these stress pathways, mimicked the effects of drug treatments. Moreover, pharmacological inhibitors of either ER or oxidative stress significantly impaired lopinavir–ritonavir-induced regulation of FGF21, but not KLB. In conclusion, the present in vitro screen study identifies the antiretroviral drugs that affect FGF21/KLB expression in human cells. The present results could have important implications for the management of comorbidities resulting from side effects of specific antiretroviral drugs for the treatment of HIV-infected patients.
Note:	Número d'acord de subvenció ISCIII/PI14-00063
Note:	Número d'acord de subvenció ISCIII/PI14-00700
Note:	Número d'acord de subvenció ISCIII/PI17-00420
Note:	Número d'acord de subvenció ISCIII/PI17-00498
Note:	Número d'acord de subvenció MINECO/SAF2014-23636
Note:	Número d'acord de subvenció MINECO/SAF2017-85722
Note:	Número d'acord de subvenció ISCIII/RD16-0025-0006
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès.
Document:	article ; recerca ; publishedVersion
Subject:	Antiretroviral drug ; FGF21 ; β-Klotho ; ER stress ; Hepatocyte ; Adipocyte
Published in:	Antimicrobial Agents and Chemotherapy, Vol. 62 (may 2018) , ISSN 1098-6596

PMID: 29661866
DOI: 10.1128/AAC.00029-18

13 p, 475.3 KB

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Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut d'Investigació Biomèdica Sant Pau
Articles > Research articles
Articles > Published articles