HDL metabolism: Influence of extracellular lipases

HDL 代谢：细胞外脂肪酶的影响

• 批准号: 8056079
• 负责人: Daniel James Rader
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056079
• 关键词: Address; Affect; Alleles; Antiatherogenic; Apolipoprotein A-I; Atherosclerosis; Biochemical; Biochemistry; Blood; Blood Circulation; Body mass index; Cells; Cellular biology; Cholesterol Esters; Cholesterol Homeostasis; Cloning; Code; Coronary Arteriosclerosis; Coronary heart disease; Data; Development; Diet; Down-Regulation; Endothelial Cells; Enzymes; Family; Future; Gene Expression; Gene Transfer; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Haplotypes; Health; Heparin; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Human Genetics; In Vitro; Individual; Insulin Resistance; Intervention; Knock-out; Knockout Mice; Lead; Learning; Lipase; Lipids; Lipoproteins; Mediating; Metabolic; Metabolism; Molecular; Mus; Names; Obesity; Persons; Phenotype; Phospholipid Transfer Proteins; Phospholipids; Physiological; Physiology; Plasma; Play; Promoter Regions; Property; Proprotein Convertases; Protein Inhibition; Proteins; Recruitment Activity; Regulation; Reporting; Risk; Role; Structure-Activity Relationship; Testing; Therapeutic; Up-Regulation; Variant; Wild Type Mouse; Work; atherogenesis; cohort; extracellular; gene environment interaction; gene interaction; genome wide association study; genome-wide; hepatic lipase; in vivo; insight; lipid transfer protein; lipoprotein lipase; macrophage; member; monocyte; novel; novel therapeutic intervention; novel therapeutics; overexpression; preclinical study; prevent; promoter; protein expression; resistance mechanism; reverse cholesterol transport; therapeutic development; translational study

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.

描述(由申请人提供)：血浆高密度脂蛋白(高密度脂蛋白)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，临床前研究一直表明，提高高密度脂蛋白的干预措施可以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“反向胆固醇运输”(2)，以及潜在地通过各种其他保护特性来预防动脉粥样硬化。然而，尽管在过去十年中取得了进展，但对高密度脂蛋白代谢和反向胆固醇运输(RCT)的分子调控仍不完全了解，其他高密度脂蛋白特性的相关性仍不确定，直接针对人类高密度脂蛋白治疗的概念仍未得到证实(3)。开发针对高密度脂蛋白的新治疗方法的有效靶点相对较少(4)。作为一种治疗策略，最先进的CETP抑制受到了质疑(5)。最近的全基因组关联研究已经开始发现与调节高密度脂蛋白水平有关的未知基因，并且已经证实作用于脂蛋白的细胞外脂肪酶亚家族中的所有三个成员，即脂蛋白脂肪酶(LPL)、肝脂酶(HL)和内皮脂肪酶(EL)，都与高密度脂蛋白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以及动脉粥样硬化风险方面起着关键作用。然而，这些脂肪酶影响高密度脂蛋白代谢的详细机制，调节其表达的环境和遗传因素，以及它们相互作用调节高密度脂蛋白代谢和功能的其他基因产物仍不完全清楚。我们认为，EL和HL在调节高密度脂蛋白代谢和动脉粥样硬化形成中的相互作用，EL和HL与脂转移蛋白胆固醇酯转运蛋白(CETP)和磷脂转运蛋白(PLTP)的相互作用，EL活性上调在肥胖胰岛素抵抗状态中的意义和机制，以及EL基因编码区和启动子上自然发生的遗传多态性对高密度脂蛋白代谢的调节。这些研究横跨生化、细胞生物学、小鼠和人类的翻译研究，以努力解决这些问题。这一脂肪酶亚家族是新的治疗开发的潜在靶点，这些研究将提供更多关于它们对高密度脂蛋白代谢和功能的影响的了解，从而使未来的治疗能够预防动脉粥样硬化。与公共健康相关：该项目的目标是提供重要的新见解，了解脂肪降解酶(脂肪酶)在调节高密度脂蛋白(“好”胆固醇)代谢和动脉粥样硬化中的作用及其与脂转移蛋白的相互作用，以及它们在调节与肥胖胰岛素抵抗状态相关的低高密度脂蛋白中的作用；以及它们与高密度脂蛋白和冠状动脉疾病的影响相关的人类遗传学。