HDL Metabolism Influence of Extracellular Phospholipases

描述（由申请人提供）：血浆高密度脂蛋白（HDL）胆固醇及其主要HDL载脂蛋白apoa - 1水平与动脉粥样硬化性心血管疾病呈负相关。血浆高密度脂蛋白胆固醇和apoa - 1水平部分取决于它们的分解代谢速率，但体内调节其分解代谢的机制仍不完全清楚。急性炎症状态（如败血症）和慢性炎症状态（如代谢综合征）都与高密度脂蛋白胆固醇和apoa - 1水平低有关，主要是由于分解代谢增加。该项目的一个主要潜在假设是，细胞外磷脂酶在炎症反应中上调，并通过水解HDL磷脂调节全身HDL代谢。我们克隆并鉴定了脂肪酶基因家族的一个新成员，我们称之为内皮脂肪酶（EL）。在这个项目的当前周期中，我们已经证明了小鼠EL的过表达由于分解代谢的增加而导致HDL的显著降低，小鼠EL的抗体抑制由于分解代谢的减少而导致HDL的增加。在这个竞争性的更新提案中，我们将重点研究EL，以更好地了解其结构-功能关系，与其他影响HDL的基因的代谢相互作用，与动脉粥样硬化的关联，及其与人体生理和病理生理的关系。具体目的1：探讨EL与其高度同源的亲缘关系LPL和HL相比，EL在脂质和脂蛋白偏好的分子基础上的差异。

DESCRIPTION (provided by applicant): Plasma levels of high-density lipoprotein (HDL) cholesterol and its major HDL apolipoprotein, apoA-I, are inversely associated with atherosclerotic cardiovascular disease. Plasma HDL cholesterol and apoA-I levels are determined in part by the rate at which they are catabolized, but the mechanisms that modulate their catabolism in vivo remain incompletely understood. Both acute inflammatory states, such as sepsis, and chronic inflammatory states, such as the metabolic syndrome, are associated with low levels of HDL cholesterol and apoA-I, primarily due to increased catabolism. A major underlying hypothesis of this project has been that extracellular phospholipases are upregulated in response to inflammation and modulate systemic HDL metabolism through hydrolysis of HDL phospholipids. We cloned and characterized a new member of the lipase gene family that we termed endothelial lipase (EL). In the current cycle of this project, we have demonstrated that overexpression of EL in mice causes markedly reduced HDL due to increased catabolism, and antibody inhibition of EL in mice causes increased HDL due to reduced catabolism. In this competing renewal proposal, we will focus our efforts on EL toward achieving a greater understanding of its structure-function relationships, metabolic interactions with other genes that influence HDL, association with atherosclerosis, and its relationship to human physiology and pathophysiology. Specific Aim 1: To investigate the differences between EL and its highly homologous relatives LPL and HL with regard to the molecular basis of the lipid and lipoprotein preferences of EL compared with LPL and HL. Specific Aim 2: To test the hypothesis that in the liver, EL interacts with HL and SR-BI to influence HDL metabolism, selective uptake of cholesterol, and reverse cholesterol transport. Specific Aim 3: To determine the effects of chronic hepatic-specific EL expression on atherogenesis in mice. To compare these results with the effects of endothelial-specific EL expression on atherosclerosis. To test the hypotheses that endothelial EL expression influences endothelial physiology. Specific Aim 4: To test the hypothesis that EL is increased in inflammatory conditions in humans and may contribute to the reduced HDL-C levels associated with these conditions. A recent editorial stated: "Perhaps the most important questions concerning endothelial lipase are: a) does it play an important role in HDL metabolism in humans, and b) does it play a significant role in atherogenesis?" This proposal addresses both of these issues and also addresses key structure-function questions and potential gene-gene interactions with regard to EL and its effects on HDL metabolism. The results of these studies should provide important new insight into the role of EL in HDL metabolism and atherogenesis.