DsbA-L对肝细胞线粒体功能及胰岛素敏感性的作用和分子机制的研究

项目名称： DsbA-L对肝细胞线粒体功能及胰岛素敏感性的作用和分子机制的研究

项目编号： No.81500621

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： 陈鸿志

作者单位： 中南大学

项目金额： 18万元

中文摘要： 近年来，大量研究揭示了线粒体功能与胰岛素敏感性的相关性。然而两者的因果关系及相互作用机制仍不清楚。我们的前期研究发现肥胖导致二硫键氧化还原酶A-类蛋白（DsbA-L）表达降低，特异性敲除小鼠肝脏DsbA-L基因加剧了高脂饮食诱导的胰岛素抵抗，酵母双杂交基因文库筛选发现并证实DsbA-L能与线粒体呼吸链相互作用。基于以上重要发现，我们认为肝脏DsbA-L表达的降低可能是肥胖导致肝细胞线粒体功能紊乱及其引起的代谢失衡的一个重要因素。在本课题中，我们将利用独特的细胞和动物模型，通过对DsbA-L相互作用蛋白的研究以及对线粒体氧化呼吸活性、氧自由基水平、胰岛素信号传导等功能的检测，阐明DsbA-L调控线粒体功能以及糖稳态的作用与机制。通过本研究，明确DsbA-L能否作为治疗肥胖和2型糖尿病的新型靶标蛋白，为胰岛素抵抗及相关代谢性疾病的诊治提供参考。

中文关键词： 胰岛素抵抗；线粒体；肥胖症；非酒精性脂肪肝；氧化应激

英文摘要： Type 2 diabetes has become a burgeoning epidemic health problem in China. While mounting evidence from both clinical and basic research suggests a strong correlation between mitochondrial dysfunction and insulin resistance, the cause-effect relationship remains elusive. Our studies demonstrate that the protein levels of disulfide bond oxidoreductase A-like protein (DsbA-L) are significantly reduced in the liver of obese human subjects and animal models of obesity. Liver-specific knockout of DsbA-L in mice exacerbated high fat diet-induced insulin resistance. By yeast 2-hybrid screening, we identified DsbA-L interaction with NDUFS2, a key component of mitochondrial respiratory chain complex I. Based on these important new findings, we hypothesize that downregulation of DsbA-L in the liver could be an important mechanism for obesity-induced hepatic mitochondrial dysfunction and insulin resistance. To test this hypothesis, we will determine whether liver-specific knockout or overexpression of DsbA-L alters mitochondrial function and glucose homeostasis. We will also elucidate the mechanism of DsbA-L action. The completion of the proposed study will not only provide new information on the mechanism underlying obesity-induced insulin resistance, but will also shed light on potential new targets for the treatment of obesity and type 2 diabetes.

英文关键词： insulin resistance;mitochondria;obesity;NAFLD;oxidative stress