Foxa3基因参与肝脏内质网应激和脂质沉积的机制研究

The worldwide epidemic of non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic diseases, is severely threatening public health. Endoplasmic reticulum stress (ERS) has been demonstrated as one of the major driving forces in the pathogenesis of NAFLD, but the detailed mechanism and effective therapeutic targets are still lacking. By taking advantage of Foxa3 wild type (WT) and knockout (KO) mice, we found that Foxa3 deficiency prevents tunicamycin induced hepatic ERS and lipid accumulation, as well as relives high fat diet induced hepatic steatosis and insulin resistance. Preliminary mechanistic studies showed that Foxa3 promotes the expression of key transcription factors of the unfolded protein response (UPR) and facilitates in the regulation of their downstream molecular networks, which predispose hepatocytes to lipid accumulation. Based on these findings, we will further elucidate the role and mechanism of Foxa3 in the regulation of ERS and lipid disorders using multiple Foxa3-overexpression and -deficient animal and cellular models. Our work would promote the molecular understanding of Foxa3 in the progression of ERS, and provide theoretic basis for implicating Foxa3 as a novel therapeutic target for treating NAFLD.

非酒精性脂肪性肝病(NAFLD)流行日益严峻，严重危害人类健康。研究表明其发病机制与肝脏内质网应激(ERS)有关，然而具体分子机制和有效干预靶点仍有待研究。本课题组利用Foxa3野生和敲除小鼠发现，Foxa3基因缺失抵抗衣霉素引起的肝脏ERS和脂质沉积，并且缓解高脂饮食诱导的脂肪肝和胰岛素抵抗。初步机制研究提示Foxa3调控ERS过程中非折叠蛋白反应(UPR)通路关键因子的转录和下游分子网络，促进肝脏脂质沉积。该项目拟在已有基础上，以Foxa3敲除小鼠以及腺病毒介导的肝脏Foxa3过表达和抑制小鼠为主要研究模型，借助原代肝细胞分离、细胞和分子生物学平台，阐明Foxa3调控ERS和脂质代谢的分子机制。本项目将有助于深入了解Foxa3参与ERS调控网络的机制，并为探索Foxa3作为NAFLD理想的干预靶点提供理论依据。

非酒精性脂肪性肝病(NAFLD)流行日益严峻，严重危害人类健康。研究表明其发病机制与肝脏内质网应激(ERS)有关，然而具体分子机制和有效干预靶点仍有待研究。该项目以FOXA3敲除小鼠以及腺病毒介导的肝脏FOXA3过表达和抑制小鼠为主要研究模型，借助原代肝细胞分离、细胞和分子生物学平台，研究发现内质网应激通过XBP1s促进FOXA3转录。利用FOXA3野生和敲除小鼠发现，FOXA3基因缺失抵抗衣霉素引起的肝脏ERS和脂质沉积，并且缓解高脂饮食诱导的脂肪肝和胰岛素抵抗。机制研究提示FOXA3调控节律因子PER1促进Srebp1c, Fasn等脂质合成基因表达，促进肝脏脂质沉积。本项目将有助于深入了解FOXA3参与内质网应激与肝脏脂质沉积调控网络的机制，为探索FOXA3作为NAFLD理想的干预靶点提供理论依据。同时，发现了转录因子PPARγ和C/EBPδ等参与脂质代谢调控，以及阿奇霉素抗生素通过氧化应激参与肥胖与脂肪肝发生发展。从而为肥胖、非酒精性脂肪肝、2 型糖尿病等代谢性疾病与肿瘤的治疗提供新的干预靶点。