肝胰岛素抵抗是2型糖尿病发病的关键因素之一。本项目组前期基于前瞻人群队列发现，血清IL-22水平在血糖升高者中显著降低，动物模型研究亦发现，过表达IL-22可显著减少高脂喂养后的肝脏脂肪沉积。但IL-22在肝脏中调控糖脂代谢的病理生理机制尚未明确，随后转录组测序提示，IL-22过表达后胆汁酸合成关键酶CYP7B1表达上调，脂肪合成相关基因显著下调，推测IL-22在肝脏中调控代谢的靶点可能是胆汁酸代谢途径CYP7B1及下游FXR信号通路。故本项目将基于前期初步数据，应用肝脏过表达IL-22小鼠、肝脏特异性Il-22ra1、Cyp7b1及Fxr敲除小鼠模型，以及肝原代细胞和肝细胞系，从体内和体外层面探讨IL-22调控胆汁酸代谢途径CYP7B1从而影响肝脏脂代谢及胰岛素敏感性的内在机制。本项目将有助于解析IL-22参与2型糖尿病的分子机制，为深入研究免疫系统与代谢系统相互调控奠定基础。

Insulin resistance is the key factor in developing of type 2 diabetes. Previously in a population based prospective study, we found that serum IL-22 level is decreased in people with higher blood glucose. In vivo study demonstrated that IL-22 overexpression significantly reduced liver steatosis in HFD mice. However, the pathological mechanism of IL-22 regulating glycolipid metabolism remains largely unclear. Further RNA-sequencing results show that the gene CYP7B1 encoding key enzyme involved in bile acids synthesis was significantly increased, while the expression of genes related with lipogenesis were significantly decreased. We thus speculate that CYP7B1 and FXR pathway may be the target of IL-22 involved in liver glycolipid metabolism. Based on these, this study will further adopt IL-22 overexpression mice, liver specific Il-22ra1 knockout, Cyp7b1 knockout and Fxr knockout mice, as well as primary hepatocyte cells and liver cells lines to investigate the mechanism of IL-22 in regulating CYP7B1 thus affecting glycolipid metabolism and insulin sensitivity both in intro and in vivo level. This study will help to elucidate the mechanism of type 2 diabetes, and to lay the foundation for intensive study of crosstalk between immune system and metabolic system.