PGC-1α调节骨骼肌脂肪酸代谢和胰岛素抵抗的分子机制

项目名称： PGC-1α调节骨骼肌脂肪酸代谢和胰岛素抵抗的分子机制

项目编号： No.81200638

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 马慧娟

作者单位： 河北省人民医院

项目金额： 23万元

中文摘要： 骨骼肌脂肪酸代谢异常导致胰岛素抵抗（IR），过氧化物酶体增生物激活受体γ共激活因子1α（PGC-1α）与脂肪酸代谢和IR关系密切。我们前期研究证实高脂喂养大鼠骨骼肌PGC-1α表达下降，伴有脂肪酸关键酶CPTⅠβ表达下降和IR。Striated activator of Rho signalling (STARS)是一种肌动蛋白结合蛋白，参与骨骼肌代谢，其在2型糖尿病患者骨骼肌表达升高，且与胰岛素敏感性呈负相关。PGC-1α可能通过调控STARS、CPTⅠβ发挥调节脂肪酸代谢和胰岛素敏感性的作用。本项目拟通过腺病毒转染，染色质免疫沉淀和荧光素酶报告基因系统等方法，从动物和细胞水平探讨PGC-1α在高脂诱导的脂肪酸代谢异常和IR形成中的分子机制，揭示PGC-1α、STARS和CPTⅠβ这一信号通路在IR形成中的作用，为阐明IR的发病机制、寻找新的药物治疗靶点提供理论依据。

中文关键词： 骨骼肌细胞；胰岛素抵抗；PGC-1α；STARS；脂肪酸氧化

英文摘要： Abnormal fatty acid metabolism in skeletal muscle leads to the development of insulin resistance (IR). Peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) plays a very important role in fatty acid metabolism and insulin resistance. Our previous studies have demonstrated that PGC-1α expression level is decreased in skeletal muscles of high-fat-fed rats, and the decrease of PGC-1α is associated with a reduced expression of CPTⅠβ which is a critical enzyme in fatty acid metabolism, and the development of IR. Striated activator of Rho signaling (STARS), an actin-binding protein, is reported to act as a regulator of skeletal muscule metablism, and increased in skeletal muscles of Type 2 diabetic patients and negatively correlated with insulin resistance. PGC-1α might regulate fatty acid metabolism through STARS and CPTⅠβ. The aim of this proposal is to investigate the mechanistic role of PGC-1a and its pathway including STARS and CPT1β, in the development of abnormal fatty acid metabolism and insulin resistance in cells and high-fat-fed rats by using Adenovirus, ChIP and luciferase gene report system etc. The findings will provide useful data to understand the molecualr mechnisam of the IR formaiton and identify potential new targets for preventing insulin resistance in humans.

英文关键词： skeletal muscle cells；insulin resistance；PGC-1α；STARS；fatty acid oxidation