PCAF乙酰化修饰XBP1s蛋白对糖尿病小鼠血糖稳态的调控研究

项目名称： PCAF乙酰化修饰XBP1s蛋白对糖尿病小鼠血糖稳态的调控研究

项目编号： No.31271260

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 孙诚

作者单位： 南通大学

项目金额： 80万元

中文摘要： 研究表明内质网应激（ERS）是肥胖导致的胰岛素抵抗及2型糖尿病（T2DM）发生、发展的重要因子之一。在ERS情况下，细胞会启动未折叠蛋白反应（UPR）以提高内质网的蛋白折叠功能。XBP1s是UPR途径中的一个重要的转录调控因子，其表达水平上调可缓解ERS。前期研究表明提高XBP1s的表达可显著地降低2型糖尿病小鼠的血糖水平，但目前对此蛋白的翻译后修饰研究较少。本课题初步研究结果表明乙酰转移酶PCAF可增加XBP1s在细胞核中的分布，上调其转录活性。另外，与正常小鼠相比，肥胖小鼠体内PCAF蛋白水平显著降低，推测PCAF可能与T2DM发展过程相关。本研究旨在阐明PCAF对XBP1s的乙酰化修饰位点，并上调糖尿病小鼠PCAF的表达，研究PCAF的上调是否可通过提高XBP1s的活性来缓解糖尿病小鼠的糖代谢异常，维持糖稳态。本项目的开展有望发现一种新的治疗T2DM的药物靶点－PCAF。

中文关键词： 2型糖尿病；肝糖异生；PCAF；PGC1a；乙酰化修饰

英文摘要： It has been demonstrated that ER stress is an important mediator responsible for obesity induced insulin resistance and type 2 diabetes. Under ER stress, cell will initiate unfolded protein response (UPR) to enfore protein folding capacity and thus to alleviate ER stress. XBP1s is a key transcriptional factor invovled in UPR and up-regulation of its expression can attenuate ER stress. Previous study show that increasing expression of XBP1s significantly decrease blood glucose levels in diabetic mice. However, little attention was paid to post-translational modification of XBP1s. Our prelimiary data show that PCAF increases XBP1s nuclear migration and transcriptional activity. futhermore, we found that there is a significant reduction in PCAF protein level in obeses animals compared with that in lean controls. The present project will be focused on which site(s) of XBP1s was acetylated by PCAF, and we expect that up-regulation of PCAF will rectify abnormal glucose metabolism and maintain glucose homeostasis in type 2 diabetic animals. The performance of this project might explore a novel drug target for curing type 2 diabetes- - acetyltransferase PCAF.

英文关键词： type 2 diabetes；hepatic gluconeogenesis；PCAF；PGC1a；acetylation