HDL metabolism: Influence of extracellular lipases

描述（由申请人提供）：血浆高密度脂蛋白（HDL）胆固醇水平与人类动脉粥样硬化性心血管疾病的风险呈负相关，临床前研究一致表明，提高HDL的干预可抑制动脉粥样硬化的进展或诱导其消退(1)。高密度脂蛋白被认为通过促进“逆向胆固醇运输”来预防动脉粥样硬化(2)，并可能通过多种其他保护特性。然而，尽管在过去十年中取得了进展，但高密度脂蛋白代谢和逆向胆固醇转运（RCT）的分子调控仍然不完全清楚，其他高密度脂蛋白特性的相关性仍然不确定，直接靶向高密度脂蛋白治疗人类的概念仍未得到证实(3)。开发针对HDL的新型治疗方法的有效靶点相对较少(4)。最先进的CETP抑制作为一种治疗策略受到质疑(5)。最近的全基因组关联研究（GWAS）已经开始确定先前未被怀疑的参与调节HDL-C水平的基因，并且还确定了作用于脂蛋白的细胞外脂肪酶亚家族的所有三个成员，脂蛋白脂肪酶（LPL），肝脂肪酶（HL）和内皮脂肪酶（EL），都与HDL-C水平的变化显著相关。显然，这个亚家族在调节高密度脂蛋白代谢和动脉粥样硬化风险方面起着关键作用。然而，这些脂肪酶影响HDL代谢的详细机制，调节其表达的环境和遗传因素，以及它们相互作用以调节HDL代谢和功能的其他基因产物仍不完全清楚。我们建议研究EL和HL在调节HDL代谢和动脉粥样硬化中的相互作用，EL和HL与脂质转移蛋白胆固醇酯转移蛋白（CETP）和磷脂转移蛋白（PLTP）的相互作用，肥胖胰岛素抵抗状态下EL活性上调的意义和机制，以及EL基因编码区和启动子中自然发生的遗传多态性对HDL代谢的调节。这些研究跨越了生物化学、细胞生物学、小鼠和人类的转化研究，以努力解决这些问题。这一脂肪酶亚家族是新型治疗开发的潜在靶点，这些研究将使人们更好地了解它们对HDL代谢和功能的影响，从而使未来的治疗能够预防动脉粥样硬化。公共卫生相关性：该项目的目标是为脂质降解酶（脂肪酶）及其与脂质转移蛋白在调节HDL（“好”胆固醇）代谢和动脉粥样硬化中的作用，以及它们在介导与肥胖胰岛素抵抗状态相关的低HDL中的作用提供重要的新见解；以及人类基因对高密度脂蛋白和冠状动脉疾病的影响。

DESCRIPTION (provided by applicant): Plasma levels of high density lipoprotein (HDL) cholesterol are inversely associated with risk of atherosclerotic cardiovascular disease in humans, and preclinical studies have consistently demonstrated that intervention to raise HDL inhibits progression or induces regression of atherosclerosis (1). HDL is believed to protect against atherosclerosis by promoting "reverse cholesterol transport" (2), as well as potentially through a variety of other protective properties. However, despite advances over the last decade, the molecular regulation of HDL metabolism and reverse cholesterol transport (RCT) remain incompletely understood, the relevance of other HDL properties remains uncertain, and the concept of directly targeting HDL therapeutically in humans remains unproven (3). There are relatively few validated targets for developing novel therapeutic approaches targeted toward HDL (4). The most advanced, CETP inhibition, has come into question as a therapeutic strategy (5). Recent genome-wide association studies (GWAS) have begun to identify previously unsuspected genes involved in regulating HDL-C levels, and have also established that all three members of the subfamily of extracellular lipases that act on lipoproteins, lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL), are significantly associated with variation in HDL-C levels. Clearly this subfamily plays a key role in modulating HDL metabolism, as well as risk of atherosclerosis. However, the detailed mechanisms by which these lipases influence HDL metabolism, the environmental and genetic factors that regulate their expression, and the other gene products they interact with to regulate HDL metabolism and function remain incompletely understood. We propose to address the interactions of EL with HL in modulating HDL metabolism and atherogenesis, the interactions of EL and HL with the lipid transfer proteins cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), the implications and mechanisms of upregulation of EL activity in the obese insulin resistant state, and the regulation of HDL metabolism through naturally-occurring genetic polymorphisms in the coding region and promoter of the EL gene. These studies span biochemical, cell biology, mouse, and human translational studies in an effort to address the questions. This subfamily of lipases is a potential target for novel therapeutic development, and these studies will provide greater understanding of their effects on HDL metabolism and function, enabling future treatments to prevent atherosclerosis. PUBLIC HEALTH RELEVANCE: The goal of this project is to provide important new insight into the role of lipid-degrading enzymes (lipases) and their interactions with lipid transfer proteins in modulating HDL ("good" cholesterol) metabolism and atherosclerosis, as well as their role in mediating the low HDL associated with the obese insulin resistant state; and their human genetics as it relates to effects on HDL and coronary artery disease.