肝脏中肉毒碱棕榈酰转移酶1A功能缺失的机理研究

CPT1A catalyzes the rate limiting step of fatty acid oxidation in mitochondria and is involved in the regulation of many physiological processes in various tissues by regulating the metabolism of fatty acid derivatives, which include many important signal molecules. However, the in vivo functional study of CPT1A in liver has not been fully performed since genetic knockout of the gene is lethal, indicating its important roles in life process. In order to investigate the physiological roles of CPT1A in liver, we have generated the CPT1A liver-specific knockout mice and our preliminary data showed that liver selective knockout of CPT1A enhanced lipid accumulation in the liver and decreased body weight and fat mass. This proposal intends to study the underlying molecular mechanism. In particular, we plan to use CPT1A liver-specific knockout mice carry out gene expression profiling and lipidomic experiments to identify the key downstream molecules and the signaling pathways in the hepatocyte caused by CPT1A defect, thus provides a theoretical basis for the prevention and treatment of obesity and its related metabolic disorders.

肉毒碱棕榈酰转移酶1(CPT1)是脂肪酸代谢的限速酶，通过调节可作为重要信号分子的脂肪酸衍生物的代谢参与调控多种组织内生理过程，但是其在重要能量调控器官肝脏中的功能还仅停留在细胞水平研究，其在体内的功能有待进一步阐明。我们已经获得CPT1A 肝脏特异性敲除小鼠模型，前期工作显示CPT1A 肝脏敲除能够增强肝脏中脂质的累积，并具有抗糖尿病的活性。本项目拟进一步继续深入研究其具体分子作用机制：以CPT1A 肝脏特异性条件敲除小鼠为研究工具，对小鼠肝脏组织的脂质累积、肝功能变化、肝脏细胞和机体代谢水平进行分析，并通过芯片、HPLC分析等技术寻找其效应蛋白分子和脂质小分子，通过细胞水平验证目标分子介导CPT1A肝脏缺陷其对机体能量代谢调控的影响后，向小鼠导入寻找到的效应分子来验证是否能够减弱或者补偿CPT1A缺陷引起的整体能量代谢状态，阐明肝脏中CPT1A缺陷引起机体能量状态改变的机理。

肉毒碱棕榈酰转移酶1(CPT1)是脂肪酸代谢的限速酶，通过调节可作为重要信号分子的脂肪酸衍生物的代谢参与调控多种组织内生理过程，但是其在重要能量调控器官肝脏中的功能还仅停留在细胞水平研究，其在体内的功能有待进一步阐明。我们已经获得CPT1A 肝脏特异性敲除小鼠模型，前期工作显示CPT1A 肝脏敲除能够增强肝脏中脂质的累积，并具有抗糖尿病的活性。本项目维持并获得背景稳定的CPT1A肝脏敲除小鼠，并且在此背景稳定的小鼠模型上，发现CPT1A肝脏缺陷能够抵抗高脂诱导的肥胖，体内脂肪组织减少，胰岛素及葡萄糖水平都保持正常，并且小鼠表现出更高的能量消耗，脂肪组织褐色化水平升高。我们分析CPT1A缺陷引起的分子变化，找到了肝脏分泌的细胞因子的改变，并提出肝脏中CPT１A缺失抵抗高脂诱导的肥胖的分子机理模型。