假激酶蛋白TRIB2在非酒精性脂肪性肝病中的作用及机制研究

Tribbles蛋白属于假激酶蛋白家族，通过发挥桥梁蛋白功能，参与机体多种能量和代谢途径的调控。然而Tribbles在非酒精性脂肪性肝病（NAFLD）中的作用及机制仍不清楚。本研究前期结果发现：1）在NAFLD模型中TRIB2表达明显升高，干扰TRIB2后可改善肝细胞内脂肪沉积，提示TRIB2与NAFLD密切相关；2）TRIB2可与线粒体脂肪酸氧化限速酶CPT1α在胞浆结合，并影响脂肪酸氧化相关基因表达及脂肪酸氧化速率。因此，我们推测TRIB2可通过结合CPT1α影响其线粒体定位进而调控NAFLD疾病进展。本研究拟以NAFLD芯片数据、动物模型及细胞模型为研究对象，利用蛋白质组学和分子生物学手段，探究TRIB2在NAFLD疾病进展中的作用，并揭示 CPT1α介导TRIB2促进NAFLD疾病进展的分子机制，为探索TRIB2作为NAFLD临床干预靶点的可行性提供理论依据。

The Tribbles pseudokinases are inactive counterparts of classical enzymes, and act as scaffolds controlling multiple aspects of energy metabolism. However, the association of Tribbles with nonalcoholic fatty liver disease (NAFLD) remains unclear. In our previous work, we found that (1) the expression of TRIB2 was markedly increased in different models of NAFLD. Furthermore, knockdown of TRIB2 expression reversed the hepatic steatosis phenotype. These results suggested that TRIB2 might be a negative regulator of the development of NAFLD. (2) TRIB2 could bind to CPT1α, the rate-limiting step of fatty acid β-oxidation, in the cytosol. Thus, we hypothesized that TRIB2 might bind to CPT1α and repress its mitochondrial translocation, and subsequently promote NAFLD. Based on those findings, using microarray data, different mouse models and cellular models of NAFLD, we will further investigate the role of TRIB2 in the development of NAFLD, the molecular mechanism by which TRIB2/CPT1α involved in the pathological progress of NAFLD, and provide new opportunities for pharmacological treatment of NAFLD.