Hypoxia‐inducible factor 2α drives hepatosteatosis through the fatty acid translocase CD36

Abstract

Background & Aims: Molecular mechanisms by which hypoxia might contribute to hepatosteatosis, the earliest stage in non-alcoholic fatty liver disease (NAFLD) pathogenesis, remain still to be elucidated. We aimed to assess the impact of hypoxia-inducible factor 2α (HIF2α) on the fatty acid translocase CD36 expression and function in vivo and in vitro. Methods: CD36 expression and intracellular lipid content were determined in hypoxic hepatocytes, and in hypoxic CD36-or HIF2α-silenced human liver cells. Histological analysis, and HIF2α and CD36 expression were evaluated in livers from animals in which von Hippel-Lindau (Vhl) gene is inactivated (Vhl f/f-deficient mice), or both Vhl and Hif2a are simultaneously inactivated (Vhl f/f Hif2α /f-deficient mice), and from 33 biopsy-proven NAFLD patients and 18 subjects with histologically normal liver. Results: In hypoxic hepatocytes, CD36 expression and intracellular lipid content were augmented. Noteworthy, CD36 knockdown significantly reduced lipid accumulation, and HIF2A gene silencing markedly reverted both hypoxia-induced events in hypoxic liver cells. Moreover livers from Vhl f/f-deficient mice showed histologic characteristics of non-alcoholic steatohepatitis (NASH) and increased CD36 mRNA and protein amounts, whereas both significantly decreased and NASH features markedly ameliorated in Vhl f/f Hif2α f/f-deficient mice. In addition, both HIF2α and CD36 were significantly overexpressed within the liver of NAFLD patients and, interestingly, a significant positive correlation between hepatic transcript levels of CD36 and erythropoietin (EPO), a HIF2α-dependent gene target, was observed in NAFLD patients. Conclusions: This study provides evidence that HIF2α drives lipid accumulation in human hepatocytes by upregulating CD36 expression and function, and could contribute to hepatosteatosis setup. This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Intrahepatic Expression of Fatty Acid Translocase CD36 Is Increased in Obstructive Sleep Apnea

“…Notably, it has been recently reported that hepatocyte-specific Srebp1 downregulation did not affect expression of genes involved in FFA uptake as Cd36 in mouse livers (30). In addition, we have just demonstrated that both CD36 expression and triglyceride content increased in mouse and human liver cells under hypoxic conditions and that silencing HIF2A gene markedly suppressed both CD36 gene upregulation and lipid accumulation in hepatocytes (14). The novelty of our present study is that both CD36 expression and the degree of steatosis are increased in livers from animal models of IH and in patients with OSA featured by nocturnal IH, supporting the notion that CD36 could be a key factor driving hepatosteatosis in OSA patients.…”

“…In particular, Greco et al showed that hepatic CD36 mRNA levels correlated with liver fat content in morbidly obese patients (11). In addition, different clinical studies have convincingly shown that the amount of both CD36 mRNA and protein was higher in the livers of biopsy-proven NAFLD patients than in subjects with histologically normal liver (12)(13)(14).…”

Hypoxia and Non-alcoholic Fatty Liver Disease

“…Regarding the role of HIFs on hepatosteatosis setup, some experimental studies revealed that both HIF1α and HIF2α were involved in hypoxia-induced lipid accumulation in hepatocytes, whereas other studies showed HIF2α as the major regulator of hepatic lipid metabolism because the absence of HIF2α, but not HIF1α, protected against lipid accumulation in the livers from mice lacking the Vhl gene (18,19). Supporting the latter, we have just demonstrated that HIF2α induced CD36 expression and function, the major driver of FFA uptake, triggering lipid accumulation in hepatocytes in vitro and in vivo, thus contributing to the hepatosteatosis onset (20). In this line, it has been demonstrated that the development of steatosis in hypoxic HepG2 cells is a consequence of increased HIF2α, which upregulated the hepatic expression of the adipose differentiationrelated protein (ADRP), also involved in FFA uptake (21).…”

“…Regarding HIF2α, a recent study revealed that IH exacerbated hepatosteatosis in mice fed HFD, which showed hepatic HIF2α overexpression along with a decreased β-oxidation and an enhanced de novo lipogenesis (22). Interestingly, silencing of hif-2α reduced lipid accumulation in hypoxic hepatocytes (20,22), pointing out to HIF2α as a key driver in hepatosteatosis setup. Recently, we have observed an upregulated expression of CD36, together with an increased triglyceride content, in livers from mice exposed to IH, pointing out that IH may also modulate FFA uptake (32).…”

Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?

“…Moreover, it has been demonstrated that hypoxia-inducible factors (HIFs) also modulate CD36 expression 103,104 . Particularly, HIF2α upregulated CD36 expression and function triggering lipid accumulation in hepatocytes in vitro and in vivo, thus contributing to the onset of hepatosteatosis, the earliest phase of NAFLD 105 .…”