Arrb2通过与SREBP2相互作用诱导酒精性肝病中的脂质代谢紊乱

酒精性肝病(ALD)是过量饮酒导致的肝脏损害性病变，脂质代谢紊乱是其早期阶段重要的病理表现。我们发现Arrb2在ALD患者及小鼠肝脏中高表达，且肝脏内呈脂质沉积的病理改变；沉默Arrb2可缓解脂质代谢紊乱；进一步发现Arrb2在ALD中促进初级胆汁酸合成；机制发现沉默Arrb2可导致SREBP2、FASN等脂质代谢关键酶的异常表达，且免疫荧光结果观察到Arrb2与SREBP2存在共定位现象。因此，我们推测Arrb2在ALD中促进脂肪酸和胆固醇沉积，进一步导致初级胆汁酸增多，共同诱导了肝脏脂质代谢紊乱，其调控机制可能与SREBP2的相互作用有关。本课题拟采用肝脏特异性Arrb2敲除小鼠与AML-12细胞，体内外探究Arrb2对肝脏脂质代谢紊乱的影响；基于代谢组学探究Arrb2对ALD小鼠肝脏脂质代谢产物的影响，同时体内外探究Arrb2的调控机制。本课题旨在为临床防治ALD提供新靶点、新思路。

Alcoholic liver disease (ALD) is a form of liver injury induced by long-term excessive alcohol abuse. Lipid metabolism disorder is a pathologic feature in the early form of ALD. We found that the expression of Arrb2 was highly expressed in the liver of ALD patients and ALD mice and the liver existed the pathological changes of steatosis and lipid deposition; Silencing Arrb2 reduced lipid metabolism disorder and Arrb2 promoted primary bile acid synthesis in ALD. In mechanism research, silencing Arrb2 lead to the abnormal expression of lipid metabolism enzymes including SREBP2、FASN and so on. Furthermore, we found Arrb2 could co-localize with SREBP2. Therefore, we speculated Arrb2 induced fatty acid synthesis and cholesterol synthesis in ALD and furthermore, Arrb2 up-regulated primary bile acid synthesis in ALD and lead to lipid metabolism disorder and the mechanism may be related to the interaction with SREBP2. To verify our hypothesis, Liver-specific Arrb2-KO mice and AML-12 cells will be used to investigate the role of Arrb2 in lipid metabolism disorder in vitro and in vivo. Silencing Arrb2 in ALD mice to observe the role of Arrb2 in lipid metabolites based on metabonomics in vivo. We also tried to investigate relevant mechanism in vitro and in vivo. This project tried to find the effective target and treatment of ALD.