Hypoxia-inducible factor 2 drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine-rich glycoprotein
Hypoxia-inducible factor 2 drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine-rich glycoprotein
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DOI：
10.1002/hep.29754
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发表时间：
2018-06-01
期刊：
影响因子：
13.5
通讯作者：
Parola, Maurizio
中科院分区：
文献类型：
--
作者：
Morello, Elisabetta;Sutti, Salvatore;Parola, Maurizio
非酒精性脂肪性肝病（NAFLD）进展的潜在机制仍不完全。缺氧和缺氧诱导因子（HIFs）与慢性肝脏疾病的发病机制有关，但HIF-2在NAFLD演变中的实际作用从未得到详细研究。在这项研究中，我们发现HIF-2在一组处于疾病进展不同阶段的NAFLD患者的肝活检组织中的细胞质和肝细胞核中选择性过表达，比例非常高（> 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HIF-2肝细胞特异性缺失的小鼠和喂食胆碱缺乏L-氨基酸定义或蛋氨酸/胆碱缺乏饮食的相关对照同窝仔中进行的实验表明，HIF-2缺失通过减少实质损伤、脂肪肝、小叶炎症和肝纤维化的发展来改善NAFLD的进展。HIF-2缺陷小鼠NAFLD进展的改善与肝细胞富含组氨酸的糖蛋白（HRGP）的产生的选择性下调有关，最近提出维持巨噬细胞M1极化。体外实验证实，肝细胞HRGP表达的上调具有缺氧依赖性和HIF-2依赖性。最后，对来自NAFLD患者的标本进行的分析表明，HRGP在所有显示HIF-2肝细胞核染色的患者中过表达，并揭示了这些患者中HIF-2和HRGP肝脏转录水平之间的显著正相关性。结论：这些结果表明，肝细胞HIF-2激活是人类和实验NAFLD的关键特征，并通过上调HRGP的产生显著促进疾病进展。（Hepatology 2018; 67：2196 - 2214）。
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-2 in the evolution of NAFLD has never been investigated in detail. In this study, we show that HIF-2 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-2 and related control littermates fed either a choline-deficient L-amino acid-defined or a methionine/choline-deficient diet showed that HIF-2 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-2-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-2-dependent. Finally, analyses performed on specimens from NAFLD patients indicated that HRGP was overexpressed in all patients showing hepatocyte nuclear staining for HIF-2 and revealed a significant positive correlation between HIF-2 and HRGP liver transcript levels in these patients. Conclusions: These results indicate that hepatocyte HIF-2 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).