E3泛素连接酶Hrd1调节肝脏糖异生的分子机制研究

Hepatic gluconeogenesis is one of the characteristics of type 2 diabetes and is considered related to various complications of diabetes. E3 ligases are involved in various diseases by mediating the specific protein degradation. However the study of E3 ligases in gluconeogenesis is very rare. The preliminary data from our proposed project has shown that the expression of E3 ligase Hrd1 was significantly decreased in the hepatocytes with gluconeogenesis and the mRNA expression of Hrd1 was upregulated by insulin. Of the interest, some other data indicated the interaction between Hrd1 and FOXO1，which is one of key transcriptional factors in gluconeogenesis. Based on these preliminary data, we’ll further study the three aspects in the future: 1) the mechanism mediating the interaction of Hrd1 and FOXO1; 2) the effect of the interaction of Hrd1 and FOXO1 on gluconeogenesis; 3) mechanism of insulin on Hrd1 transcriptional expression. The findings of our study will demonstrate the effects of E3 ligases mediated protein degradation on gluconeogenesis.

肝脏糖异生活性异常升高是2型糖尿病重要特征，也是造成相关并发症的主要原因。由E3泛素连接酶介导的蛋白质降解影响不同疾病的发生发展，是近年来医学研究的热点。但是有关E3泛素连接酶对肝脏糖异生的调控机制研究较少。本课题的前期研究表明，E3泛素连接酶Hrd1在发生糖异生的肝细胞中表达明显降低；Hrd1与糖异生关键转录调控因子FOXO1可能存在直接相互作用；胰岛素可显著上调Hrd1的mRNA表达。在此基础上，本课题将利用动物实验和细胞实验，围绕以下三个方面开展工作：1) Hrd1与FOXO1直接相互作用以及介导后者经蛋白酶体降解的分子机制；2）Hrd1-FOXO1之间相互作用关系对肝脏糖异生的影响；3）胰岛素对Hrd1表达的转录调控机制等。本课题的意义在于深入探讨E3连接酶介导的泛素化降解对肝脏糖异生的影响，为今后以此为靶点开发糖尿病防治的临床手段奠定理论基础。