内皮脂酶抑制高胆固醇血症和动脉粥样硬化的作用机制研究

Hypercholesterolemia is one of the most important independent risk factors for atherosclerosis, Endothelial lipase (EL) is a key determinant of lipid metabolism thereby modulating the development of atherosclerosis. In our recent study, we have reported that increased hepatic expression of endothelial lipase significantly inhibits cholesterol diet-induced hypercholesterolemia and atherosclerosis in transgenic rabbits. However, the mechanisms of EL regulating lipid metabolism and inhibiting atherosclerosis remain unclear. In the present project, we will investigate the following questions using transgenic rabbit models and cultured cells to clarify the molecular mechanisms of EL on lipid metabolism and atherosclerosis:1) to examine the mechanisms of EL on lipid metabolism and atherosclerosis using EL transgenic and Watanabe heritable hyperlipidemic (WHHL) rabbits. 2) to examine the functional roles of EL with enzymatic activity compared with EL without enzymatic activity but with binding activity in regulating lipoprotein metabolism using cultured cells expressing different EL; 3) to study how EL (with enzymatic activity vs. without enzymatic activity but with binding function) on lipid metabolism and atherosclerosis in vivo using the WHHL rabbits model. These studies will not only provide novel insights into understanding EL functions in regulating lipid metabolism and atherosclerosis but also open a new possibility for treating hyperlipidemia and atherosclerosis using EL as a potential target.

高胆固醇血症是动脉粥样硬化发生发展的重要独立危险因子之一，内皮脂酶（EL）是脂质代谢的关键酶之一，在动脉粥样硬化的发生发展中具有重要作用。我们前期研究发现家兔过表达EL显著抑制高胆固醇血症和动脉粥样硬化，但EL调节脂质代谢和抑制动脉粥样硬化的分子机制仍然未知。本课题拟采用EL转基因家兔和渡边遗传性高脂血症（WHHL）家兔模型：（1）研究EL调节脂质代谢和抑制动脉硬化的作用机制；（2）利用过表达有酶活性和非活性EL的细胞模型，阐明EL对VLDL/LDL的结合和摄取过程中分子作用机制；（3）利用表达酶活性及非活性EL的WHHL家兔模型，揭示EL分子对脂质代谢和动脉硬化的影响。本课题旨在阐明EL调节脂质代谢的作用及其机制，进一步揭示EL与动脉粥样硬化的关系，为高脂血症及动脉粥样硬化的防治提供新的靶点和理论依据。

动脉粥样硬化是心血管疾病的主要病理基础，高胆固醇血症是动脉粥样硬化最重要的独立危险因子之一。研究其发病机制，对心血管疾病的防治具有重大意义。内皮脂酶（EL）是脂质代谢的关键酶之一，在动脉粥样硬化的发生发展中具有重要作用。内皮脂酶是脂质代谢的关键酶之一，在动脉硬化的发生、发展中具有重要作用。本课题研究发现家兔过表达EL可以显著抑制高胆固醇血症和动脉粥样硬化，主要的机制是增强了β-VLDL的分解代谢；性激素参与了EL介导的脂质代谢和动脉硬化，雄激素的存在很可能是EL的降低血脂和动脉粥样硬化保护作用所必需的。通过研究EL在脂质代谢中的作用及其机制，进一步揭示EL与动脉硬化的关系，为高脂血症及动脉粥样硬化的防治提供新的靶点和理论依据。