Reciprocal effects of antiretroviral drugs used to treat HIV infection on the fibroblast growth factor 21/β-Klotho System

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 -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.

This research was supported by grants from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III ([ISCIII] PI14/00063, PI14/00700, PI17/00420, and PI17/ 00498) and the Ministerio de Economía y Competitividad ([MINECO] SAF2014-23636 and SAF2017-85722), cofinanced by the European Regional Development Fund (ERDF) and Red de Investigación en SIDA (RD16/0025/0006), ISCIII, Spain. R.M. was supported by a PFIS PhD scholarship from AES, ISCIII, MINECO, Spain. T.Q.-L. was supported by a CONACyT (National Council for Science and Technology in Mexico) PhD scholarship. J.V. and J.M.G.-E. are “Juan de la Cierva” (MINECO, Spain) and “Sara Borrell” (ISCIII, Spain) postdoctoral researchers, respectively.