Rey Esther, Meléndez-Rodríguez Florinda, Marañón Patricia, Gil-Valle Miriam, Carrasco Almudena G, Torres-Capelli Mar, Chávez Stephania, Del Pozo-Maroto Elvira, Rodríguez de Cía Javier, Aragonés Julián, García-Monzón Carmelo, González-Rodríguez Águeda
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid, Spain.
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Liver Int. 2020 Oct;40(10):2553-2567. doi: 10.1111/liv.14519. Epub 2020 Jun 10.
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.
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 -deficient mice), or both Vhl and Hif2a are simultaneously inactivated (Vhl Hif2α -deficient mice), and from 33 biopsy-proven NAFLD patients and 18 subjects with histologically normal liver.
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 -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 Hif2α -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.
This study provides evidence that HIF2α drives lipid accumulation in human hepatocytes by upregulating CD36 expression and function, and could contribute to hepatosteatosis setup.
缺氧可能导致肝脂肪变性，这是非酒精性脂肪性肝病（NAFLD）发病机制的最早阶段，其分子机制仍有待阐明。我们旨在评估缺氧诱导因子2α（HIF2α）在体内和体外对脂肪酸转运蛋白CD36表达和功能的影响。
在缺氧的肝细胞以及缺氧的CD36或HIF2α沉默的人肝细胞中测定CD36表达和细胞内脂质含量。对von Hippel-Lindau（Vhl）基因失活的动物（Vhl缺陷小鼠），或Vhl和Hif2a同时失活的动物（Vhl Hif2α缺陷小鼠）的肝脏，以及33例经活检证实的NAFLD患者和18例肝脏组织学正常的受试者的肝脏进行组织学分析，并评估HIF2α和CD36表达。
在缺氧的肝细胞中，CD36表达和细胞内脂质含量增加。值得注意的是，CD36基因敲低显著减少脂质积累，而HIF2A基因沉默明显逆转了缺氧肝细胞中缺氧诱导的这两个事件。此外，Vhl缺陷小鼠的肝脏表现出非酒精性脂肪性肝炎（NASH）的组织学特征，且CD36 mRNA和蛋白量增加，而在Vhl Hif2α缺陷小鼠中这两者均显著降低，NASH特征明显改善。此外，NAFLD患者肝脏中HIF2α和CD36均显著过表达，有趣的是，在NAFLD患者中观察到CD36肝转录水平与促红细胞生成素（EPO，一种HIF2α依赖性基因靶点）之间存在显著正相关。
本研究提供的证据表明，HIF2α通过上调CD36表达和功能驱动人肝细胞中的脂质积累，并可能促成肝脂肪变性的发生。
