肝星状细胞中Hic-5缺失促进NAFLD中胆固醇降解的机制研究

胆固醇在肝细胞中蓄积会对肝细胞产生脂毒性，诱导炎症因子释放，促进NAFLD进展。肝星状细胞（HSCs）是否通过调控胆固醇代谢参与NAFLD及其机制仍不清楚。课题组发现肝脏中，Hic-5特异性表达于HSCs；在小鼠高脂饮食NAFLD模型中，肝组织Hic-5表达上调；敲除Hic-5不仅抑制IL-1β、TNF-α等炎症因子和YAP1等调控基因表达，也减轻肝脏脂质蓄积，脂质蓄积减轻与胆固醇降解增强密切相关。据此认为HSCs中Hic-5的缺失可减轻NAFLD炎症反应和胆固醇蓄积。课题组拟：1.利用基因敲除鼠证实Hic-5调控NAFLD胆固醇降解的作用；2.利用细胞共培养阐明HSCs中Hic-5/YAP1调控肝细胞胆固醇降解的机制；3.探讨Hic-5在NAFLD病人治疗中的靶点价值。项目将通过Hic-5对胆固醇代谢的调控阐明HSCs与肝细胞交互在NAFLD中的作用及其机制，为治疗NAFLD提供新策略。

The accumulation of cholesterol in hepatocytes can cause lipotoxicity, induce the release of inflammatory factors, and promote the progression of NAFLD. Whether hepatic stellate cells (HSCs) participate in NAFLD by regulating cholesterol metabolism and its mechanism remains unclear. We found that Hic-5 was specifically expressed in HSCs, and up-regulated in NAFLD mice fed with high-fat diet, while knockout of Hic-5 not only inhibited the expression of inflammatory factors such as IL-1β, TNF-α and regulatory genes such as YAP1, but also reduced liver lipid accumulation, which was closely related to the enhancement of cholesterol degradation. Thus, we hypothesized that the deletion of Hic-5 in HSCs can reduce the inflammation and cholesterol accumulation in NAFLD models. Our plan is divided into three parts: 1. Use genetically engineered mice to confirm the role of Hic-5 in cholesterol degradation in NAFLD; 2. To clarify the mechanism of Hic-5/YAP1 regulating cholesterol degradation in HSCs by cell co-culture; 3. Investigate the value of Hic-5 as a therapeutic target of NAFLD. This project will clarify the role and mechanism of HSCs-Hepatocyte cross-talk in NAFLD through the effect of Hic-5 on cholesterol metabolism, and provide a new strategy for the treatments of NAFLD.