非酒精性脂肪肝是导致人类慢性肝损伤的主要病因，严重威胁人类健康。非酒精性脂肪肝的发生是由于脂质输入与脂质输出的失衡导致。多种免疫因子参与了非酒精性脂肪肝的发生，但是目前IL-27信号在非酒精性脂肪肝中的研究几乎空白。申请人所在的课题组近年来一直从事IL-27在肝脏免疫和肿瘤免疫中的调控作用的研究。而申请人近期研究显示，IL-27可以直接靶向脂肪细胞，调节其脂质裂解及UCP1介导的代谢产热过程，进而抑制肥胖及胰岛素抵抗的发生。并且，IL-27信号缺失小鼠非酒精性脂肪肝的发病显著加重。所以，我们的关键科学问题是：非酒精性脂肪肝病中IL-27的细胞来源是什么？IL-27是作用到免疫细胞上还是直接靶向肝脏细胞？其调控肝脏脂质代谢的分子机制是什么？这些研究将首次阐明IL-27信号通路对非酒精性脂肪肝的调控作用及分子机制，填补该领域的空白，并为非酒精性脂肪肝的治疗提供新的靶点。

Non-alcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver dysfunction and one of the main threats for human health. Previous studies showed that the induction of NAFLD was due to the disruption of lipid metabolism homeostasis. Immune cells and immune molecules were found to be involved in the pathogenesis of NAFLD. IL-27 is a pleiotropic cytokine in regulating immune responses, but its role in NAFLD is unknown. Our group has been studying the role of IL-27 in liver injury and tumor immunity for many years. Our recent work shows that IL-27 directly targets the IL-27R in adipocytes, promotes the lipolysis and UCP1 mediated thermogenesis, hereby suppress the development of obesity and insulin resistance. In the meantime, we also found that IL-27Ra KO mice developed more severe NAFLD than WT littermates. So our scientific question is what's the cellular source of IL-27 in NAFLD? Whether IL-27 could directly regulate the lipid metabolism of hepatocytes or through immune cells? What’s the molecular mechanism? These studies will uncover the role and molecular mechanism of IL-27 signaling in regulating NAFLD and provide a new potential therapeutic target for the treatment of NAFLD.