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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
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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 |
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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 |
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