Hypoxia-inducible factor alfa drives hepatosteatosis through the fatty acid translocase CD36
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2020-05-20
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WILEY-BLACKWELL
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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.
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Rey, E., Meléndez-Rodríguez, F., Marañón, P., Gil-Valle, M., Carrasco, A. G., Torres-Capelli, M., Chávez, S., Del Pozo-Maroto, E., Rodríguez de Cía, J., Aragonés, J., García-Monzón, C., & González-Rodríguez, Á. (2020). Hypoxia-inducible factor 2α drives hepatosteatosis through the fatty acid translocase CD36. Liver international : official journal of the International Association for the Study of the Liver, 40(10), 2553–2567. https://doi.org/10.1111/liv.14519
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