基于Sirt1的抗炎特性研究小檗碱调节糖脂代谢的分子机制

项目名称： 基于Sirt1的抗炎特性研究小檗碱调节糖脂代谢的分子机制

项目编号： No.81473391

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： 尚文斌

作者单位： 南京中医药大学

项目金额： 71万元

中文摘要： 清热解毒中药黄连的有效成分小檗碱具有显著的抑制机体炎症反应的效应，并能改善肥胖和糖尿病的糖脂代谢紊乱和胰岛素抵抗，其作用靶点和生物学效应与体内的去乙酰化酶沉默信息调节因子1（Sirt1）的抗炎特性以及其调控的多种糖脂代谢相关信号通路基本一致，表明小檗碱可能通过Sirt1的介导发挥其药理效应。 本课题以脂肪细胞和巨噬细胞的炎症反应为切入点，体外运用siRNA干扰Sirt1细胞和体内运用Sirt1基因敲除小鼠，借助多种细胞和分子生物学手段和技术，探明小檗碱的抗炎和调节糖脂代谢的作用是否由Sirt1介导，并明确小檗碱依赖于Sirt1所调节的下游炎症信号通路以及与糖脂代谢相关的信号蛋白和转录因子，进一步运用蛋白质组学技术，探寻新的乙酰化分子靶点。 本研究从新的角度更加深入阐明小檗碱抗炎作用和治疗代谢性疾病的机制，既对中医药抗糖尿病方药的研究思路做出探索，也为小檗碱多种药理效应的机制研究提供线索。

中文关键词： 小檗碱；沉默信息调节因子1；胰岛素抵抗；糖脂代谢；脂肪细胞

英文摘要： Berberine is a natural compound isolated from Chinese herbs Coptis chinensis, which exerts significant anti-inflammatory action on body and improves dysfunction of glucose and lipid metabolism and insulin resistance in obesity and diabetes. The biological action and its targets related to glucose and lipid metabolism is similar to those of silent information regulator 1(Sirt1), a deacetylase enzyme which also exerts anti-inflammatory effects and improves insulin sensitivity. It implies that pharmalogical effects of berberine are mediated by Sirt1, In this study, the role of Sirt1 in berberine' anti-inflammatory property and regulating effects on glucose and lipid metabolism will be explored in Sirt1 knockdown adipocytes and macrophages or in Sirt1 knockout mice. Furthermore, the effects of berberine on inflammatory signal transduction pathway and signaling molecules or transcription factors related to glucose and lipid metabolism which are controlled by Sirt1 will be investigated. Finally, new deacetyled targets induced by berberine in dependent of Sirt1 will be identified with technology of proteomics. The results of this study will be helpful to elucidate the mechanism underlining berberine' effects on inflammation and metabolic diseases in new viewpoint. It will provide a clue for research on diabetes in Chinese medicine and for potential mechanism of berberine' s multiple pharmalogical actions.

英文关键词： berberine;Sirt1;insulin resistance;glucose and lipid metabolism;adipocyte