PCAF干扰PGC-1a转录活性对2型糖尿病小鼠肝糖异生调控作用的研究

项目名称： PCAF干扰PGC-1a转录活性对2型糖尿病小鼠肝糖异生调控作用的研究

项目编号： No.81471037

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： 孙诚

作者单位： 南通大学

项目金额： 75万元

中文摘要： 翻译后修饰是调节蛋白活性的重要方式之一。PGC-1a是肝糖异生过程中的一种关键转录共激活因子，其活性异常升高可导致高糖血症。控制PGC-1a的转录活性是一种治疗高糖血症的有效手段。PCAF是一种蛋白乙酰转移酶,可乙酰化修饰多种蛋白因子。我们初步研究发现2型糖尿病小鼠肝脏中PCAF表达下降，同时伴随PGC-1a乙酰化水平的下降,提示PCAF可能是体内乙酰化修饰PGC-1a的关键乙酰转移酶。随后细胞研究结果证实PCAF确实可乙酰化修饰PGC-1a，并可导致PGC-1a转录活性降低。本课题旨在阐明PCAF干预PGC-1a转录活性的分子机制，并且拟通过提高2型糖尿病小鼠肝脏PCAF的表达,降低PGC-1a的转录活性，从而改善糖尿病小鼠的糖代谢紊乱，缓解高糖血症。本项目的开展有望确立PCAF表达降低是导致2型糖尿病小鼠高血糖症的因素之一,并且PCAF可能作为一种新的筛选治疗高糖血症的药物靶点。

中文关键词： 2型糖尿病；乙酰转移酶PCAF；肝糖异生；过氧化物酶体增殖物激活受体共激活因子1a；高糖血症

英文摘要： Post-translational modification is an important manner to regulate protein activity. PGC-1alpha? is a key transcriptional coactivator for hepatic gluconeogenesis. Ectopic stimulation of PGC-1alpha?activity in liver results in hyperglycemia. Therefore interference of PGC-1alpha activity is a useful strategy for treating hyperglycemia. PCAF is an acetyltranferase and it has been showed that PCAF could acetylate many kinds of cytokines and thus affect their activities. Our preliminary data showed that PCAF expression was reduced in type 2 diabetic mouse liver and acetylated PGC-1alpha was decreased as well, indicating PCAF may be a key acetyltransferase in vivo for acetylating PGC-1alpha. Further in vitro experiments revealed that PCAF really acetylates PGC-1alpha and leads to repression of PGC-1alpha transcriptional activity. In the current projects, we aim to elucidate the involved molecular mechanisms responsible for PCAF-mediated repression of PGC-1alpha activity. In the following experiments, we will increase PCAF expression in diabetic mouse liver and investigate whether PCAF over-expression causes interference of PGC-1alpha activity, and thus to rectify the impaired glucose metabolism and ameliorates hyperglycemia in type 2 diabetic mice. Taken together, we speculate that PCAF expression reduction might be a causative factor for developing hyperglycemia in type 2 diabetic mice. Furthermore, PCAF acetyltransferase might be a novel drug target for developing new agents against hyperglycemia.

英文关键词： type 2 diabetes;PCAF acetyltransferase;hepatic gluconeogenesis;PGC-1a;hyperglycemia