LAUSR

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. Conclusions: 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).