Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Department of Medical Sciences, University of Turin, Turin, Italy.
Hepatology. 2018 Jun;67(6):2196-2214. doi: 10.1002/hep.29754. Epub 2018 Apr 19.
Mechanisms underlying progression of nonalcoholic fatty liver disease (NAFLD) are still incompletely characterized. Hypoxia and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of chronic liver diseases, but the actual role of HIF-2α in the evolution of NAFLD has never been investigated in detail. In this study, we show that HIF-2α is selectively overexpressed in the cytosol and the nuclei of hepatocytes in a very high percentage (>90%) of liver biopsies from a cohort of NAFLD patients at different stages of the disease evolution. Similar features were also observed in mice with steatohepatitis induced by feeding a methionine/choline-deficient diet. Experiments performed in mice carrying hepatocyte-specific deletion of HIF-2α and related control littermates fed either a choline-deficient L-amino acid-defined or a methionine/choline-deficient diet showed that HIF-2α deletion ameliorated the evolution of NAFLD by decreasing parenchymal injury, fatty liver, lobular inflammation, and the development of liver fibrosis. The improvement in NAFLD progression in HIF-2α-deficient mice was related to a selective down-regulation in the hepatocyte production of histidine-rich glycoprotein (HRGP), recently proposed to sustain macrophage M1 polarization. In vitro experiments confirmed that the up-regulation of hepatocyte HRGP expression was hypoxia-dependent and HIF-2α-dependent. Finally, analyses performed on specimens from NAFLD patients indicated that HRGP was overexpressed in all patients showing hepatocyte nuclear staining for HIF-2α and revealed a significant positive correlation between HIF-2α and HRGP liver transcript levels in these patients.
These results indicate that hepatocyte HIF-2α activation is a key feature in both human and experimental NAFLD and significantly contributes to the disease progression through the up-regulation of HRGP production. (Hepatology 2018;67:2196-2214).
非酒精性脂肪性肝病（NAFLD）进展的机制仍不完全明确。缺氧和缺氧诱导因子（HIFs）已被认为与慢性肝病的发病机制有关，但 HIF-2α 在 NAFLD 演变中的实际作用从未被详细研究过。
本研究显示，在不同疾病进展阶段的 NAFLD 患者肝活检组织中，HIF-2α 选择性地在细胞质和细胞核中过度表达（>90%）。在喂食蛋氨酸/胆碱缺乏饮食诱导的脂肪性肝炎小鼠中也观察到类似的特征。在携带肝细胞特异性 HIF-2α 缺失的小鼠和相关对照同窝仔鼠中进行的实验表明，无论喂食胆碱缺乏 L-氨基酸定义饮食还是蛋氨酸/胆碱缺乏饮食，HIF-2α 缺失均可通过减少实质损伤、脂肪肝、小叶炎症和肝纤维化的发展来改善 NAFLD 的进展。HIF-2α 缺陷小鼠 NAFLD 进展的改善与肝细胞产生组氨酸丰富糖蛋白（HRGP）的选择性下调有关，最近提出该蛋白可维持巨噬细胞 M1 极化。体外实验证实，肝细胞 HRGP 表达的上调依赖于缺氧和 HIF-2α。最后，对 NAFLD 患者标本的分析表明，在所有显示肝细胞核 HIF-2α 染色的患者中 HRGP 过度表达，并显示这些患者的 HIF-2α 和 HRGP 肝转录水平之间存在显著的正相关。
这些结果表明，肝细胞 HIF-2α 的激活是人类和实验性 NAFLD 的一个关键特征，通过上调 HRGP 的产生，显著促进了疾病的进展。
