磷酸酶PP2A催化亚基C在肝脏脂肪代谢中的功能研究

Extra calories and low physical activity carry an increased risk of health problem. The liver is a major target site for insulin which regulates glucose and lipid metabolism. In the postprandial state, the liver takes up the excess carbohydrates to lipids via de novo lipogenesis. Protein Phosphatase 2A (PP2A) is a ubiquitously expressed family of serine/threonine phosphatases, which plays critical roles in the regulation of many cellular functions. There is a close relation between glucose and lipid. Previous studies have the beneficial effects of the liver PP2A deficiency in Alb-cre mice, which exhibited an enhanced the ability to clear glucose from the peripheral circulation and activated the insulin signaling. Moreover, the knockout mice have no obvious abnormality in the liver on high fat diet. It implies PP2A may be an important component in regulating the lipid metabolism. In the project, we will analyze the mechanism underlying PP2A in the lipid metabolism and provide new drug therapy for the treatment of insulin resistance syndrome, such as obesity and type 2 diabetes.

不健康的饮食和生活习惯（吃得多、动得少）是威胁人类健康的一大关键因素。肝脏作为胰岛素重要的靶器官，参与调节了糖代谢以及脂肪代谢过程。餐后，摄入过多的碳水化合物，肝脏会通过脂质新生将多余糖转化成脂肪。PP2A（2A型蛋白磷酸酶）是体内广泛表达的丝氨酸/苏氨酸磷酸酶。糖代谢和脂肪代谢之间有着密切的关系。本项目在前期研究工作中发现在体内缺失PP2A会增加胰岛素敏感性，提高糖稳态，激活胰岛素通路；缺失PP2A的小鼠喂食高脂后，肝脏中没有出现明显的脂肪肝现象。这些都暗示PP2A可能是参与调节肝脏脂肪代谢的一个重要分子。本项目将系统分析PP2A在脂肪代谢过程中的作用，揭示其机制，并为寻找治疗肥胖、二型糖尿病之类的胰岛素抵抗综合征的药物靶点提供新方向。