Hypoxia‐inducible factor 2α drives hepatosteatosis through the fatty acid translocase CD36
Esther Rey, Florinda Meléndez‐Rodríguez, Patricia Marañón, Miriam Gil‐Valle, Almudena García-Carrasco, Mar Torres‐Capelli, Stephania Chávez, Elvira Del Pozo-Maroto, Javier Rodríguez de Cía, Julián Aragonés, Carmelo García‐Monzón, Águeda González‐Rodríguez
Abstract
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.