Examinando por Autor "del Pozo Maroto, Elvira"

Mostrando 1 - 1 de 1

Hypoxia-inducible factor alfa drives hepatosteatosis through the fatty acid translocase CD36
(WILEY-BLACKWELL, 2020-05-20) Rey, Esther; Meléndez Rodríguez, Florinda; Marañón, Patricia; Gil Valle, Miriam; García Carrasco, Almudena; Torres Capelli, Mar; Chávez, Stephania; del Pozo Maroto, Elvira; Rodríguez de Cía , Javier; Aragonés, Julián; García Monzón, Carmelo; González Rodríguez, Águeda
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 (Vhlf/f -deficient mice), or both Vhl and Hif2a are simultaneously inactivated (Vhlf/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 Vhlf/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 Vhlf/f Hif2αf/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.