Abstract
ABSTRACTFollowing 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.
Highlights
Following antiretroviral therapy, HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor 21 (FGF21)
Among the antiretroviral drugs tested in HepG2 hepatic cells, all protease inhibitors (PIs), including the lopinavir-ritonavir 4:1 combination, elicited a robust induction of FGF21 expression (Fig. 1A)
We found that the same drugs that induced FGF21 expression and KLB repression induced the endoplasmic reticulum (ER) stress/oxidative stress markers C/EBP-homologous protein 10 (CHOP10) and HSPA5; the one exception was the absence of an effect of elvitegravir on HSPA5
Summary
HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor 21 (FGF21). The paradoxically high FGF21 levels in HIV patients are associated with a downregulation of the molecular mediator of cellular FGF21 action, KLB This scenario, which is reminiscent of “FGF21 resistance,” is analogous to the situation found in obesity and type 2 diabetes [14, 15]. It has been suggested that alterations in the FGF21 endocrine system involving liver and adipose tissues could be a major mechanism responsible for eliciting metabolic alterations in HIV patients [8, 13, 16] In this context, it has recently been reported that high FGF21 levels in HIV patients are significantly associated with altered bone homeostasis [17], consistent with previous indications of potential deleterious effects of high FGF21 levels on bone in experimental rodent models [18]. Inflammation in adipose tissue, a common condition in obesity, diabetes, and HIV lipodystrophy, may contribute to impaired FGF21 responsiveness in adipocytes
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