IL-27信号通路对非酒精性脂肪肝的调控作用及分子机制

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.

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。

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。..在本项研究中，我们发现在非酒精性脂肪肝模型中肝细胞中IL-27亚基EBI-3,P28以及IL-27受体Ra (wsx-1)表达增多。利用wsx-1 KO基因敲除小鼠以及Alb-cre-wsx-1flox/flox条件性基因敲除小鼠，我们发现在高脂饮食诱导的非酒精性脂肪肝模型中，IL-27信号缺失的小鼠脂肪肝程度显著加重，肝脏中甘油三酯水平增加，肝损伤加重，肝脏中炎症细胞浸润增加。体内体外实验表明，IL-27信号的缺失促进肝脏中p38MAPK信号通路的激活，应用p38MAPK抑制剂可以有效降低基因缺陷小鼠肝细胞中甘油三酯的累积，改善脂肪肝。IL-27信号还通过抑制CD4 T细胞介导的巨噬细胞浸润从而间接抑制脂肪肝的进展。..这些结果表明IL-27信号对非酒精性脂肪肝具有重要的抑制作用。这为通过细胞因子途径调控非酒精性脂肪肝提供了坚实的理论基础，也为基于细胞因子的免疫疗法提供了新的潜在靶点。研究成果于2020年，2021分别发表在Frontiers in Immunology及Nature上。