HDL metabolism: Influence of extracellular lipases

HDL 代谢：细胞外脂肪酶的影响

• 批准号: 7820923
• 负责人: Daniel James Rader
• 金额: $ 4.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820923
• 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; Heparin; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Human Genetics; Hydrolysis; 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 therapeutic intervention; novel therapeutics; overexpression; preclinical study; prevent; promoter; protein expression; public health relevance; 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）：高密度脂蛋白 (HDL) 胆固醇的血浆水平与人类动脉粥样硬化性心血管疾病的风险呈负相关，临床前研究一致证明，提高 HDL 的干预措施可抑制动脉粥样硬化的进展或诱导其消退 (1)。 HDL 被认为可以通过促进“胆固醇反向转运”(2) 以及潜在的多种其他保护特性来预防动脉粥样硬化。然而，尽管过去十年取得了进展，但 HDL 代谢和反向胆固醇转运 (RCT) 的分子调节仍不完全清楚，其他 HDL 特性的相关性仍不确定，并且直接靶向人类 HDL 治疗的概念仍未得到证实 (3)。用于开发针对 HDL 的新型治疗方法的经过验证的靶标相对较少 (4)。最先进的 CETP 抑制作为一种治疗策略已受到质疑 (5)。最近的全基因组关联研究 (GWAS) 已开始鉴定以前未被怀疑的参与调节 HDL-C 水平的基因，并且还确定作用于脂蛋白的细胞外脂肪酶亚家族的所有三个成员，即脂蛋白脂肪酶 (LPL)、肝脂肪酶 (HL) 和内皮脂肪酶 (EL)，与 HDL-C 水平的变化显着相关。显然，该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发挥着关键作用。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，以及与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。我们建议解决EL与HL在调节HDL代谢和动脉粥样硬化形成中的相互作用，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活性上调的含义和机制，以及通过调节HDL代谢 EL 基因编码区和启动子中天然存在的遗传多态性。这些研究涵盖生物化学、细胞生物学、小鼠和人类转化研究，旨在解决这些问题。该脂肪酶亚家族是新型治疗开发的潜在靶标，这些研究将更好地了解它们对 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。公共健康相关性：该项目的目标是提供重要的新见解，了解脂质降解酶（脂肪酶）的作用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 HDL 中的作用；及其人类遗传学，因为它与高密度脂蛋白和冠状动脉疾病的影响有关。

项目成果

Lipidomic analyses of female mice lacking hepatic lipase and endothelial lipase indicate selective modulation of plasma lipid species.

对缺乏肝脂肪酶和内皮脂肪酶的雌性小鼠的脂质组学分析表明血浆脂质种类的选择性调节。

• DOI: 10.1007/s11745-014-3907-6
• 发表时间: 2014
• 期刊: Lipids
• 影响因子: 1.9
• 作者: Yang,Yanbo;Kuwano,Takashi;Lagor,WilliamR;Albert,CarolynJ;Brenton,Siobhan;Rader,DanielJ;Ford,DavidA;Brown,RobertJ
• 通讯作者: Brown,RobertJ

Novel ENU-induced point mutation in scavenger receptor class B, member 1, results in liver specific loss of SCARB1 protein.

• DOI: 10.1371/journal.pone.0006521
• 发表时间: 2009-08-05
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Stylianou IM;Svenson KL;VanOrman SK;Langle Y;Millar JS;Paigen B;Rader DJ
• 通讯作者: Rader DJ

Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits.

• DOI: 10.1161/atvbaha.113.302802
• 发表时间: 2014-05
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Mehta N;Qamar A;Qu L;Qasim AN;Mehta NN;Reilly MP;Rader DJ
• 通讯作者: Rader DJ

Characterization of the lipolytic activity of endothelial lipase.

• 发表时间: 2002-06
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: M. McCoy;Gwo-Shing Sun;D. Marchadier;C. Maugeais;J. M. Glick;D. Rader

Overexpression of apolipoprotein F reduces HDL cholesterol levels in vivo.

• DOI: 10.1161/atvbaha.108.177105
• 发表时间: 2009-01
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Lagor WR;Brown RJ;Toh SA;Millar JS;Fuki IV;de la Llera-Moya M;Yuen T;Rothblat G;Billheimer JT;Rader DJ
• 通讯作者: Rader DJ