SIRT7 抑制非酒精性脂肪肝病发生发展的机制研究

项目名称： SIRT7 抑制非酒精性脂肪肝病发生发展的机制研究

项目编号： No.81470841

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 贺明

作者单位： 上海交通大学

项目金额： 73万元

中文摘要： 非酒精性脂肪性肝病（NAFLD）在我国的发病率呈上升趋势,阐明其发病机制具有重要理论和应用价值。SIRT7是沉默信息调节因子（sirtuin）蛋白家族成员，是在肝脏中高表达的一类NAD+ 依赖的组蛋白去乙酰化酶。新近，本课题组发现，全身性SIRT7基因敲除（KO）小鼠在正常饮食状态下出现NAFLD，而恢复SIRT7的表达可抑制KO小鼠NAFLD的发生，并减轻肝脏内质网应激（ERS）。本项目拟在此基础上，构建肝脏特异性SIRT7基因敲除小鼠，进一步明确 SIRT7在肝细胞脂代谢及NAFLD发生发展中的作用；在细胞水平，利用生物信息学和分子生物学技术阐明SIRT7减轻ERS，进而抑制NAFLD发生的分子机制以及SIRT7在ERS反应中的表达调控；探讨SIRT7作为NAFLD治疗靶点的可能性。此研究不仅揭示了SIRT7在肝脏代谢中的功能及机制，而且有望为NAFLD的预防和治疗提供新的科学依据。

中文关键词： 非酒精性脂肪性肝病；SIRT7；内质网应激；脂质代谢；转录调控

英文摘要： The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing in China and its pathogenesis is poorly understood, and therapeutic options are limited. SIRT7, a member of silent information regulator (sirtuin) protein family, is a nuclear NAD+ -dependent histone deacetylase and highly expressed in liver. The function of SIRT7 in metabolism is not clear. Preliminary data were recently obtained to demonstrate that SIRT7-deficient mice fed a chow diet developed NAFLD. Moreover, the reconstitution of SIRT7 in SIRT7 KO mice reversed the fatty liver phenotype and suppressed ER stress (ERS). Based on these results, three specific aims which will be pursued are as follows: First, establish the liver specific SIRT7 gene knockout mice to determine the role of SIRT7 in the lipid metabolism of liver cells; Second, in vitro, investigate the molecular mechanism by which SIRT7 suppresses ERS, prevents NAFLD and SIRT7 is regulated by ERS using bioinformatics and molecular biology techniques; Third, test the possibility that SIRT7 maybe a potential therapeutic target. The completion of this study will advance our knowledge about the physiological function of SIRT7 in regulation liver metabolic homeostasis and provide a molecular basis for developing new therapeutic and preventive strategies.

英文关键词： nonalcoholic fatty liver disease (NAFLD);sirtuin7;Endoplasmic Reticulum stress (ERS);lipid metabolism;transcriptional regulation