盐酸小檗碱对代谢异常引起的线粒体功能紊乱的调节机制研究

项目名称： 盐酸小檗碱对代谢异常引起的线粒体功能紊乱的调节机制研究

项目编号： No.81500660

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 赵志云

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 近年来，线粒体功能紊乱在代谢异常疾病发病机制中所起的作用逐渐成为了研究的热点。人群研究显示2型糖尿病或胰岛素抵抗的病人线粒体功能下降。盐酸小檗碱是一种从植物中发现的天然生物碱，本人所在课题组首先在临床上验证其有着降血糖、降血脂、降体重等多种调节代谢作用，副作用少，有良好的药用前景。本课题组已经证实小檗碱在体内有增加能量消耗、提高线粒体解偶联水平的作用，但其对线粒体的具体调节机制和分子靶点仍不明确。本申请人进一步研究了小檗碱在体内调节线粒体功能的机制，发现了其对线粒体关键代谢酶和呼吸链复合物的蛋白有调节作用，并且乙酰化等转录后调控机制也参与其中。本申请人在此研究基础上，计划继续深入研究小檗碱调节线粒体功能的分子机制，寻找其作用的具体靶点蛋白，再以去乙酰化酶SIRT活性为核心，分析乙酰化等转录后调控机制对上述蛋白活性的影响，阐述其在药效中发挥的作用，为代谢性疾病的治疗提供新的分子靶点和思路。

中文关键词： 代谢紊乱；线粒体；2型糖尿病；小檗碱；转录后修饰

英文摘要： Recently, the role of mitochondrial dysfunction in metabolic disorder diseases has gained increasing attention. Epidemiological study of the series of rapid growing metabolic disorders such as type 2 diabetes or insulin resistance all demonstrate significant mitochondrial function down-regulation, indicating that as a critical and basal organelle that is in charge of terminal steps of glucose and lipid metabolism, mitochondrion might be crucial in revealing the mechanism of such metabolic disorders. Hydrochloride (BBR) is a kind of alkaloid compound purified from herbs, which has been used to treat type 2 diabetes for several years with its outstanding features of few side effects. Previous study revealed its effect on ameliorating hyperglycemia, hyperlipidemia and obesity. Our group was the first to verify BBR’s effect on increasing energy expenditure and mitochondrial uncoupling effect in vivo. However, the exact protein targets of BBR and its regulation mechanism in treating metabolic diseases are still elusive. For mechanism study, we find evidence of BBR regulating mitochondrial function through mitochondrial metabolic enzymes or respiratory chain proteins. Epigenetic regulation would be critical to mitochondrial function. As a newly risen field of epigenetic regulation, post-transcriptional modification such as acetylation and succinylation has shed light on the control of target metabolic enzymes according to our recent data. Furthermore, factors which regulate acetylation may also participate in such pathways. SIRT1 (Sirtuin type 1) is a member of the NAD+ dependent histone deacetylase. As our data indicates, it might be an essential target for interpreting effect of BBR by its epigenetic regulation. In this study, SIRT1 would be our research target, and experiments would be conducted to find out the related protein target of BBR in treating metabolic diseases, as well as revealing the regulation of post-transcriptional modification during treatment.

英文关键词： metabolic disorder;mitochondrial;Type 2 Diabetes;berberine;posttranscriptional modification