Perilipin-5蛋白调控肝星状细胞激活和高脂饮食性非酒精性脂肪肝的机制

项目名称： Perilipin-5蛋白调控肝星状细胞激活和高脂饮食性非酒精性脂肪肝的机制

项目编号： No.31471330

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 汤有才

作者单位： 郑州大学

项目金额： 80万元

中文摘要： 肝纤维化与非酒精性脂肪性肝病（NAFLD）密切相关，其发生机制尚不清楚，更缺乏有效的治疗手段。肝星状细胞（HSC）激活是肝纤维化发生的中心步骤。静态HSC含大量脂肪滴，脂肪滴丢失是其激活的重要标志，并顺势诱导纤维化相关基因表达。Perilipin 5（Plin5），一种脂滴结合蛋白，可促进HSC内脂肪滴的形成。瘦素可减少HSC内脂肪积累。我们前期研究发现:1、Plin5随着HSC激活表达下降；2、外源性Plin5可恢复HSC内脂肪储存并抑制HSC生长和激活；3、Plin5可降低HSC瘦素的表达。我们推测Plin5可阻断瘦素及其信号传导，调控脂肪代谢和抑制HSC的激活，阻止和逆转肝纤维化，影响NAFLD的发展过程。在前期研究基础上，本课题拟继续以肝纤维化及肥胖动物模型为平台，结合体外细胞培养，探讨Plin5调控肝星状细胞激活和高脂饮食性脂肪性肝病的机制，为治疗脂肪肝合并纤维化提供新的靶点。

中文关键词： 分子机制；Perilipin-5；肝星状细胞；肝纤维化；非酒精性脂肪肝病

英文摘要： Liver fibrogenesis is closely associated with nonalcoholic fatty liver disease (NAFLD). Its mechanism remains elusive and no effective therapeutic strategy for this disease is available. Hepatic stellate cell (HSC) activation is a central event for the development of liver fibrosis. Quiescent HSCs contain lipid droplets (LDs), whose depletion upon activation, in turn, induces a fibrogenic gene program,leading to an increase of α-SMA and α (1)Ⅰ collagen. Loss of lipid droplets is a hallmark of HSC activation. Perilipin 5 (Plin 5), a lipid droplet-binding protein,improves formation of LDs in HSC. Leptin redues accumulation of LDs in HSC. Our pilot data show here that: 1, Plin 5 is highly expressed in quiescent HSCs and dramatically decreased following HSC activation, concomitant with depletion of LDs. 2, Lentiviral Plin 5 transduction inhibits growth and activation of passaged WT HSCs and augmented intracellular lipid accumulation, including triglyceride (TG) and FA. 3, Exogenous Plin5 reduces gene expression of leptin in HSC. To further investigate the role of Plin 5 in regulating HSC activation and diet-induced non-alcoholic fatty liver disease, and address the underlying mechanisms, we propose three specific aims: 1. Determine the function domains by which Plin 5 modulates lipid metabolism and examine its role in regulating gene expression and signaling pathway related to lipid metabolisms.2.Test whether Plin 5 regulates lipid metabolism and inhibits HSC growth by blocking leptin and its signaling pathway. 3. Evaluate the role of Plin 5 in inhibiting liver fibrogenesis and ameliorating non-alcoholic fatty liver disease in Plin 5 knockout (Plin 5-/-) mice models. These findings will elucidate the mechanisms by which Plin5 modulates hepatic stellate cell activation and nonalcoholic fatty liver disease, and provides novel targets for therapeutic strategy of fatty liver disease along with hepatic fibrosis.

英文关键词： molecular mechanism;Perilipin-5;hepatic stellate cell;hepatic fibrosis;nonalcoholic fatty liver disease