PGC1α调控IL10影响肝脏胆固醇代谢的分子机制及其在NASH形成中的作用

非酒精性脂肪性肝炎（NASH）以肝细胞脂质积累伴随炎症及不同程度纤维化为特征，其发病机制未完全明了。我们前期研究发现NASH小鼠肝细胞中PGC1α表达水平显著下降，肝脏特异性高表达PGC1α能显著减轻肝组织炎症、凋亡、纤维化及肝细胞胆固醇含量，且抑炎因子IL10表达上调，但机制不明。本项目拟采用激光共聚焦显微镜、染色质免疫共沉淀、靶基因过表达与siRNA沉默等技术以及NAFLD细胞模型、肝脏特异性PGC1α高表达及敲除小鼠模型，确定PGC1α靶向正调控IL10表达，升高的IL10通过促进肝细胞胆固醇代谢，经抑制IRE1α-XBP1-Caspase-2、TNFα和Fas依赖的死亡信号和JNK1信号通路参与NASH发病的作用及具体分子机制，具有较高创新性及临床意义。

Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte fat accumulation accompanied by inflammation and varying degrees of fibrosis, but its pathogenesis is poorly understood. Our previous studies revealed that the expression of PGC1α was significantly decreased in mouse model of NASH. By using a hepatocyte-specific PGC1α overexpression (LivPGC1α) mouse model, we demonstrated that PGC1α significantly ameliorated hepatic inflammation, apoptosis, fibrosis and cholesterol levels. Furthermore, the expression of anti-inflammatory factor IL10 was upregulated. However, the pathogenesis remains unknown. In this research project, by using laser confocal microscopy, chromatin immunoprecipitation, target gene overexpression and siRNA-dependent silence or knockout as well as NAFLD cell models or LivPGC1α mouse model and hepatocyte-specific PGC1α knockout mouse models, we try to research and determine the roles and mechanisms the PGC1α regulates IL10 to promote cholesterol metabolism, which further inhibit IRE1α-XBP1-Caspase-2, TNFα/Fas-dependent death signals and JNK1 signaling pathways involved in NASH pathogenesis and molecular mechanism. The findings of this project will possess high originality and clinical significance.