Ⅱ型脂肪酸合成酶抑制剂对糖尿病状况下线粒体功能的影响

项目名称： Ⅱ型脂肪酸合成酶抑制剂对糖尿病状况下线粒体功能的影响

项目编号： No.31200620

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 陈聪

作者单位： 西安交通大学

项目金额： 23万元

中文摘要： 近年来，以Ⅱ型脂肪酸合成酶(FAS Ⅱ)为靶点筛选出了大量的广谱抗菌性抑制剂。然而近期研究发现，线粒体中脂肪酸合成途径与细菌FAS Ⅱ具有高度地保守性，因此，我们推测抑制剂的使用会造成线粒体的功能缺陷。我们首次利用线粒体FAS Ⅱ与抗菌性抑制剂进行分子对接模拟，初步从理论上证明了这一可能性。值得关注的是，线粒体FAS Ⅱ是体内硫辛酸合成的重要途径。我们通过脂肪细胞实验和糖尿病Goto-Kakizaki大鼠实验发现硫辛酸能够有效缓解糖尿病发生中的线粒体功能缺陷。于是我们推测硫辛酸的使用可能缓解线粒体FAS Ⅱ抑制剂的危害。因此我们将在脂肪细胞和糖尿病大鼠模型中检测线粒体FAS Ⅱ的表达变化的特点、规律和抑制剂的影响，着重观察抑制剂的使用对线粒体生成和功能的影响，并深入研究硫辛酸的使用对线粒体FAS Ⅱ抑制剂造成的线粒体功能缺陷的保护效果。

中文关键词： 线粒体脂肪酸合成酶；硫辛酸；线粒体功能障碍；胰岛素抵抗；C75

英文摘要： Recently, several inhibitors of prokaryotic fatty acid synthesis Ⅱ(FAS Ⅱ) enzymes have been found and considered as promising antibiotics. However, it is known fatty acid synthesis pathway in mitochondrial and bacterial FASⅡ are similarly and highly conservative. Therefore, we propose that FAS Ⅱ enzyme inhibitors may induce mitochondrial dysfunction and damage. We have docked the bacterial anti-FAS Ⅱ drugs into mitochondrial FASⅡ, predicted a series of potential inhibitors could lead to mitochondrial dysfunction. Interestingly, studies have suggested that mitochondrial FAS Ⅱ is capable of generating octanoyl-ACP substrate for lipoic acid synthesis. In our previous studies, we treated 3T3-L1 adipolytes and Goto-Kakizaki diabetic rats with α-lipoic acid (LA), and found that LA is effective on improving mitochondrial dysfunction. Thus, we hypothesize that LA could alleviate the risk of mitochondrial FASⅡ inhibitors on diabetic mitochondria. In the present proposal, we will study the characterization and regulatory mechanisms mitochondrial FASⅡin normal and type Ⅱ diabetes models. Specifically, we will investigate the mitochondrial biogenesis and function in 3T3-L1 adipolytes and Goto-Kakizaki diabetic rats with mitochondrial FASⅡ inhibitors and study the protective effect of LA by combining LA and mitochondrial

英文关键词： mitochondrial FAS II；lipoic acid；mitochondrial dysfunction；insulin resistance；C75