Cargando…

Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System

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 F...

Descripción completa

Detalles Bibliográficos
Autores principales: Moure, Ricardo, Domingo, Pere, Villarroya, Joan, Gasa, Laura, Gallego-Escuredo, José M., Quesada-López, Tania, Morón-Ros, Samantha, Maroto, Alberto F., Mateo, Gracia M., Domingo, Joan C., Villarroya, Francesc, Giralt, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971578/
https://www.ncbi.nlm.nih.gov/pubmed/29661866
http://dx.doi.org/10.1128/AAC.00029-18
_version_ 1783326300467888128
author Moure, Ricardo
Domingo, Pere
Villarroya, Joan
Gasa, Laura
Gallego-Escuredo, José M.
Quesada-López, Tania
Morón-Ros, Samantha
Maroto, Alberto F.
Mateo, Gracia M.
Domingo, Joan C.
Villarroya, Francesc
Giralt, Marta
author_facet Moure, Ricardo
Domingo, Pere
Villarroya, Joan
Gasa, Laura
Gallego-Escuredo, José M.
Quesada-López, Tania
Morón-Ros, Samantha
Maroto, Alberto F.
Mateo, Gracia M.
Domingo, Joan C.
Villarroya, Francesc
Giralt, Marta
author_sort Moure, Ricardo
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5971578
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher American Society for Microbiology
record_format MEDLINE/PubMed
spelling pubmed-59715782018-05-31 Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System Moure, Ricardo Domingo, Pere Villarroya, Joan Gasa, Laura Gallego-Escuredo, José M. Quesada-López, Tania Morón-Ros, Samantha Maroto, Alberto F. Mateo, Gracia M. Domingo, Joan C. Villarroya, Francesc Giralt, Marta Antimicrob Agents Chemother Antiviral Agents 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. American Society for Microbiology 2018-05-25 /pmc/articles/PMC5971578/ /pubmed/29661866 http://dx.doi.org/10.1128/AAC.00029-18 Text en Copyright © 2018 Moure et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Antiviral Agents
Moure, Ricardo
Domingo, Pere
Villarroya, Joan
Gasa, Laura
Gallego-Escuredo, José M.
Quesada-López, Tania
Morón-Ros, Samantha
Maroto, Alberto F.
Mateo, Gracia M.
Domingo, Joan C.
Villarroya, Francesc
Giralt, Marta
Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System
title Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System
title_full Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System
title_fullStr Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System
title_full_unstemmed Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System
title_short Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/β-Klotho System
title_sort reciprocal effects of antiretroviral drugs used to treat hiv infection on the fibroblast growth factor 21/β-klotho system
topic Antiviral Agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971578/
https://www.ncbi.nlm.nih.gov/pubmed/29661866
http://dx.doi.org/10.1128/AAC.00029-18
work_keys_str_mv AT mourericardo reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT domingopere reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT villarroyajoan reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT gasalaura reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT gallegoescuredojosem reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT quesadalopeztania reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT moronrossamantha reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT marotoalbertof reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT mateograciam reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT domingojoanc reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT villarroyafrancesc reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem
AT giraltmarta reciprocaleffectsofantiretroviraldrugsusedtotreathivinfectiononthefibroblastgrowthfactor21bklothosystem