泛素化连接酶VprBP/DCAF1通过SIRT1调控肝脏甘油三酯代谢的作用与机制研究

非酒精性脂肪肝病（NAFLD）已成为我国最主要的慢性肝病之一，然而其病理生理机制尚未明确。既往研究表明，沉默信息调节因子2相关酶1(SIRT1)在肝脏甘油三酯代谢中起着至关重要的作用。前期工作中，利用免疫沉淀-质谱的筛选，并结合免疫共沉淀等方法，首次发现: 泛素化连接酶VprBP/DCAF1通过同SIRT1蛋白相互作用，促进其蛋白降解。进一步的研究表明，高脂饮食喂养肥胖小鼠、瘦素缺陷ob/ob肥胖小鼠的肝脏组织中VprBP表达显著增加，同时SIRT1的蛋白表达显著降低。在小鼠原代肝脏细胞中，利用腺病毒过表达VprBP基因后，SIRT1蛋白减少，细胞内甘油三酯含量增加。由此提示，肥胖时，肝脏中VprBP通过促进SIRT1的蛋白降解，促进甘油三酯的沉积和脂肪肝的发生发展。因此，我们将在上述发现基础上，进一步研究VprBP在NAFLD发病过程中的作用，为脂肪肝的治疗寻找新的靶点。

NAFLD is one of the main chronic liver diseases, well the pathophysiologic mechanism is remain unclear. Recent researches exposed silent information regulation 2 related enzyme-1(sirtuin1) plays an important role in hepatic triglyceride metabolism. In our formal study, using ip-mass and immune-co-ip methods, we find reciprocal combination between E3 ligase VprBP/DCAF1 and SIRT1, promoting its protein degradation. Furthermore, we find the expression of VprBP/DCAF1 was augmented in the liver of HFD-induced obesity mice and leptin deficient ob/ob mice，meanwhile the protein level of SIRT1 decreased remarkably. Adenovirus transfection produced the over expression of VprBP in the murine Primary hepatocyte, the protein level of SIRT1 reduced markedly and the concentration of TG was elevated. It suggested that hepatic VprBP could induce the protein degradation of SIRT1, promoting the TG deposition and development of NAFLD. Based on these results, we intend to investigate the role of E3 ligase VprBP during the development of NAFLD, and search new targets for the treating of fatty liver diseases.