SIRT7 抑制非酒精性脂肪肝病发生发展的机制研究

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.

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。

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H3K18Ac组蛋白去乙酰化酶。本研究中，我们构建了SIRT7基因敲除（KO）小鼠，发现KO小鼠发生明显的类似于人类的脂肪肝病变，而利用AAV8病毒载体恢复肝细胞中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）。实验表明，SIRT7可以通过作用于染色质抑制内质网应激（ERS），进而减缓NAFLD的发生。而在机制方面，我们发现，ERS可以上调SIRT7表达，而SIRT7可以通过与转录因子Myc结合募集到核糖体蛋白启动区，进而抑制核糖体蛋白基因的表达，减轻ERS。通过药物抑制或基因敲减Myc可以明显减轻 SIRT7缺失导致的NAFLD的发生。更为重要的是，SIRT7肝细胞特异性过表达可以通过抑制ERS明显逆转高脂饮食导致的NAFLD。总之，本工作揭示了SIRT7可以与Myc结合并抑制其转录作用，而且SIRT7可以通过减轻ERS抑制NALFD的发生。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。