LOX-1/Cullin7介导的泛素化修饰在脂肪细胞胰岛素抵抗中的作用及机制研究

Insulin resistance is the main pathogenesis of multiple metabolic abnormalities.The impairment of insulin signaling pathway is a major cause of insulin resistance. However, it is unclear the regulatory mechanisms of the post-translational modifications on insulin signaling molecules that leading impairment of signaling pathway. Our pilot study showed that thepost-translational degradation of IRS1 (insulin receptor substrate 1), Glut4 (glucose transporter 4) and perilipin were increased in FFA(free fatty acid) treated adipocyte. The expression of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) and Cullin7 (an E3 ubiquitiation ligase) were up-regulated in adipose tissue of insulin resistance mice induced by high fat diet. Therefore, we hypothesis that LOX-1/Cullin7 may be mediated the post-translational modification of insulin signal molecules. We will be planning to explore the important/potential role of Cullin7 in adipocyte insulin resistance. Furthermore, we will investigate the underlying mechanism that LOX-1 promotes insulin resistance (ubiquitiation mediated by Cullin7). This study contributes to the understanding of the pathogenesis of insulin resistance, and provides new strategies to seek for the new drugs target.

胰岛素抵抗导致多种代谢性疾病，其发生的主要原因是胰岛素信号通路受损。翻译后修饰异常可导致胰岛素信号通路受损，但确切机制尚不清楚。我们预实验发现：自由脂肪酸诱导脂肪细胞中IRS1（胰岛素受体底物1）、Glut4（葡萄糖转运体4）以及perilipin（围脂滴蛋白）蛋白翻译后降解；胰岛素抵抗小鼠脂肪组织中LOX-1（植物凝集素样氧化性低密度脂蛋白受体-1）与Cullin7（E3泛素连接酶）表达升高；因此推测：胰岛素抵抗时LOX-1/Cullin7可能介导胰岛素信号通路分子的翻译后泛素化修饰。本项目拟通过在体动物、细胞实验和临床病例研究，阐明Cullin7在胰岛素抵抗中的重要作用；从泛素化修饰角度探讨LOX-1促胰岛素抵抗的作用和机制。本研究将有助于阐明高脂饮食情况下脂肪细胞胰岛素抵抗的机制，为寻找胰岛素抵抗治疗的新靶点奠定基础。

胰岛素抵抗导致多种代谢性疾病的发生，其原因主要是胰岛素信号通路受损。翻译后修饰异常可导致胰岛素信号通路受损，但确切机制尚不清楚。LOX-1作为FFA或Ox-LDL的受体，在脂质代谢中有重要作用，但是LOX-1是否参与胰岛素抵抗的发生尚不清楚。预实验发现：自由脂肪酸诱导脂肪细胞中IRS1（胰岛素受体底物1）和Glut4（葡萄糖转运体4）蛋白翻译后降解；胰岛素抵抗小鼠脂肪组织中LOX-1（植物凝集素样氧化性低密度脂蛋白受体-1）与Cullin7（E3泛素连接酶）表达升高。本项目拟通过在体动物和细胞实验研究LOX-1促胰岛素抵抗的作用和机制。结果发现：（1）LOX-1介导了高脂诱导胰岛素抵抗的发生；（2）LOX-1通过cullin7调控IRS1和Glut4蛋白的泛素化。本项目首次研究了LOX-1在脂肪细胞胰岛素抵抗中的作用及机制，有助于阐明高脂饮食情况下脂肪细胞胰岛素抵抗的机制，为寻找胰岛素抵抗治疗的新靶点奠定基础。