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Mechanism of ApoA1 Lipidation by ABCA1 in HDL biogenesis

HDL生物合成中ABCA1对ApoA1脂化的机制

基本信息

批准号：
9102483
负责人：
Jonathan D Smith
金额：
$ 40.76万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102483
关键词：
ATP binding cassette transporter 1 Apolipoprotein A-I Apolipoproteins A Apolipoproteins B Atherosclerosis Binding Biochemical Biogenesis Biological Assay Biological Markers CETP gene Cardiovascular Diseases Cell Membrane Proteins Cell membrane Cell surface Cells Cholesterol Clinical Consensus Coronary heart disease Data Dependence Development Epidemiologic Studies Excretory function Failure Future Genetic High Density Lipoprotein Cholesterol High Density Lipoproteins Human Incidence Knowledge Lead Ligands Lipids Liver Mediating Membrane Proteins Modeling Molecular Mutation N-terminal Nicotinic Acids Pathway interactions Peripheral Pharmaceutical Preparations Pharmacotherapy Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Phosphatidylinositols Phosphatidylserines Phospholipids Play Process Production Proteins Proton Pump Randomized Reaction Resistance Risk Role Serum Signal Transduction Site Structure Testing Therapeutic Tissues base biophysical analysis cardiovascular disorder prevention cardiovascular disorder risk crosslink genetic variant inhibitor/antagonist insight mouse model novel novel therapeutics overexpression prevent protective effect public health relevance reverse cholesterol transport stoichiometry translocase vacuolar H+-ATPase

项目摘要

DESCRIPTION (provided by applicant): High levels of high density lipoprotein-cholesterol (HDL-C) are associated with lowered risk for cardiovascular disease (CVD) in epidemiological studies. However, recent genetic and drug studies have shown that HDL-C itself is probably not causal in reducing CVD risk. Instead, a consensus is building that HDL functions may protect against CVD, and that treating for the biomarker of HDL-C may not always coincide with increased HDL function. One of the functions of HDL that may play a role in its protective effect is its role in the reverse cholesterol transport (RCT) pathway, in which cholesterol is removed from peripheral tissues and transferred to the liver for excretion. HDL and its major protein constituent, apolipoprotein A-I (apoA-I), are critical components of this process. In the first ste of the RCT pathway, lipid-poor apoA-I acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCA1, generating nascent HDL through a mechanism which is not understood at the molecular level. ABCA1 has two well characterized activities, the outward translocation of phosphatidylserine, and the cell surface binding of its ligand apoA-I. We recently characterized a third activity of ABCA1, the ability to unfold apoA-I's N-terminal helical hairpin.In Aim 1, we explore our novel finding that phosphatidylinositol phosphates (PIPs) play a role in nascent HDL biogenesis. In Aim 2, we explore the mechanism by which ABCA1 helps partially unfold apoA-I on the cell surface, including the role of our novel finding of ABCA1 mediated acidification of apoA-I on the cell surface. Successful completion of the proposed studies will increase our knowledge of the mechanism of de novo HDL production, which may yield insights into new strategies to increase HDL biogenesis and HDL function, and aid in the prevention of CVD.

描述（由申请人提供）：流行病学研究显示，高水平的高密度脂蛋白胆固醇 (HDL-C) 与心血管疾病 (CVD) 风险降低相关。然而，最近的遗传和药物研究表明，HDL-C 本身可能并不是降低 CVD 风险的原因。相反，人们正在达成共识，即 HDL 功能可以预防 CVD，并且 HDL-C 生物标志物的治疗可能并不总是与 HDL 功能增强同时发生。 HDL 可能在其保护作用中发挥作用的功能之一是其在反向胆固醇转运 (RCT) 途径中的作用，在该途径中，胆固醇从外周组织中去除并转移到肝脏进行排泄。 HDL 及其主要蛋白质成分载脂蛋白 A-I (apoA-I) 是该过程的关键组成部分。在 RCT 途径的第一步中，缺乏脂质的 apoA-I 通过细胞膜蛋白 ABCA1 作为细胞胆固醇和磷脂的受体，通过一种在分子水平上尚不清楚的机制产生新生 HDL。 ABCA1 有两个明确的活性：磷脂酰丝氨酸的向外易位，以及其配体 apoA-I 的细胞表面结合。我们最近表征了 ABCA1 的第三个活性，即展开 apoA-I 的 N 端螺旋发夹的能力。在目标 1 中，我们探索了磷脂酰肌醇磷酸 (PIP) 在新生 HDL 生物合成中发挥作用的新发现。在目标 2 中，我们探索了 ABCA1 帮助在细胞表面部分展开 apoA-I 的机制，包括我们新发现的 ABCA1 介导细胞表面 apoA-I 酸化的作用。成功完成拟议的研究将增加我们对 HDL 从头产生机制的了解，这可能有助于了解增加 HDL 生物发生和 HDL 功能的新策略，并有助于预防 CVD。