非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病（NAFLD）的进展形式,与终末期肝病和心血管事件密切相关,然而发病机制尚不清楚。我们对NASH小鼠肝脏RNA测序和蛋白质组定量分析,发现NASH肝脏中I型干扰素信号通路被广泛激活,其中IFIT3最为显著。在肝脏过表达Ifit3可改善NASH饮食诱导的肝脏炎症及纤维化,敲除Ifit3则加重NASH；机制方面，我们在体外肝细胞中发现IFIT3有抗凋亡作用。提示肝细胞内I型干扰素信号通路激活/IFIT3上调，可能是对抗NASH的代偿保护。本研究将在上述工作基础上,联合多种技术手段：1）在体内和体外对肝细胞I型干扰素受体激活与敲除、IFIT3过表达与敲除,系统阐述I型干扰素信号通路/IFIT3对NASH发病的作用；2）深入探讨IFIT3调控肝细胞凋亡的机制。对上述问题的阐释,将加深对NASH发病机制的认识,并为NASH治疗手段的研发提供潜在靶标。

Abstract: Nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD, is closely associated with end-stage liver disease and increases the risk for cardiovascular disease. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. We performed RNA-seq and quantitative proteomic profiling studies on the livers from healthy and diet-induced NASH mice, which revealed genes involved in type I interferon signaling were remarkably induced in NASH. Ifit3 is most impressive among the interferon stimulated genes. Hepatic Ifit3 overexpression attenuated diet-induced NASH, while IFIT3 deficiency elicited the opposite effects, supporting a critical role of IFIT3 in NASH. Mechanistically, we demonstrated IFIT3 cell-autonomously protected hepatocyte from apoptosis in vitro. Our data suggest type I interferon response and upregulation of IFIT3 in hepatocyte as part of a negative feedback mechanism that gating the amplification of NASH phenotype. Based on these impressive findings, we plan to: 1) delineate the roles of type I interferon -IFIT3 in NASH pathogenesis through manipulating hepatic type I interferon signaling and Ifit3 expression; 2) dissect the molecular mechanisms underlying IFIT3 regulation of hepatocyte apoptosis. Our proposed work will seek to elucidate new mechanisms underlying NASH progress and hope to shed light on developing novel therapeutic targets.