The role of endothelial lipase in pathogenesis of atherosclerosis : A novel therapeutic target for raising HDL cholesterol

最近，我们从血管形成过程中的内皮细胞中克隆了脂肪酶基因家族的新成员内皮细胞衍生脂肪酶（EL）。为了研究EL在脂蛋白代谢和动脉粥样硬化中的作用，我们培育了转基因和敲除EL小鼠，并分析了其脂质谱。EL转基因和敲除小鼠的表征显示，在遗传小鼠模型中，EL表达与循环HDL-C水平呈负相关。为了研究EL在动脉粥样硬化进程中的作用，我们制造并分析了apoE/EL双敲除小鼠。EL/apoE双基因敲除小鼠与apoE单基因敲除小鼠相比，动脉粥样硬化病变面积减少了70%。尽管血浆胆固醇升高，EL/apoE双敲除小鼠显示主动脉斑块大小明显减小。EL在体内可能通过影响循环高密度脂蛋白胆固醇和非酶桥接功能而具有动脉粥样硬化作用。内皮细胞中的EL mRNA被与血管疾病病因相关的炎症因子上调，包括TNF-α和IL-1β。免疫组织化学分析显示，EL在人冠状动脉粥样硬化斑块的内皮细胞、平滑肌细胞以及浸润细胞中表达。在EL基因敲除小鼠中，LPS注射的急性炎症反应不影响HDL-C水平，而在对照野生型小鼠中，LPS注射降低了HDL-C水平。因此，EL的上调可能是全身性炎症中HDL-C降低的原因。综上所述，EL的存在和EL的调控表达可能在动脉粥样硬化等冠状动脉疾病的发病机制以及血管壁脂质代谢中具有独特的功能作用。因此，EL被认为是提高HDL-C和预防动脉粥样硬化的药物干预的一个有吸引力的治疗靶点。

Recently, we have cloned endothelial cell-derived lipase (EL), a new member of the lipase gene family, from endothelial cells during vascular formation. To investigate role of EL in lipoprotein metabolism and atherosclerosis, we generated transgenic and knockout mice of EL, and analyzed the lipid profiles. Characterization of EL transgenic and knockout mice revealed that EL expression correlates inversely with circulating HDL-C levels in genetic mouse models. To investigate the role of EL in atherosclerotic progression, apoE/EL double knockout mice were generated and analyzed. Atherosclerotic lesion area was decreased by 70% in the EL/apoE double knockout mice compared with the apoE single knockout mice. Despite the increase in plasma cholesterol, EL/apoE double knockout mice showed significantly decreased aortic plaque sizes. EL may have atherogenic actions in vivo through its effect on circulating HDL cholesterol and non-enzymatic bridging function. EL mRNA was upregulated in endothelial cells by inflammatory cytokines implicated in vascular disease etiology, including TNF-α and IL-1β. Immunohistochemical analysis revealed that EL was expressed in endothelial and smooth muscle cells, as well as infiltrating cells, in the atheromatous plaque in human coronary arteries. In EL knockout mice, acute inflammatory reaction by LPS injection did not affects the HDL-C levels, although HDL-C was reduced by LPS injection in control wild type mice. Thus, upregulation of EL may account for the reduced HDL-C in systemic inflammation. Taken together presence of EL and regulated expression of EL may have unique functional roles in the pathogenesis of coronary artery diseases such as atherosclerosis as well as in lipid metabolism in the vessel wall. Therefore, EL is considered to be an attractive therapeutic target for pharmacological intervention to raising HDL-C and to prevent atherosclerosis.