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（由适用提供）：在流行病学研究中，高密度脂蛋白 - 胆固醇（HDL-C）与心血管疾病（CVD）的风险降低有关。但是，最近的遗传学和药物研究表明，HDL-C本身可能不是降低CVD风险的因果关系。取而代之的是，共识正在建立HDL功能可以预防CVD，而治疗HDL-C的生物标志物可能并不总是与HDL功能增加相吻合。 HDL的功能之一可能在其受保护作用中发挥作用的功能是其在反向胆固醇转运（RCT）途径中的作用，其中将胆固醇从外周组织中去除并转移到肝脏中以进行极端。 HDL及其主要蛋白质构建体Apolipoylotoin A-I（ApoA-I）是该过程的关键组成部分。在RCT途径的第一个Ste中，脂肪贫穷的ApoA-I通过细胞膜蛋白ABCA1充当细胞胆固醇和磷脂的受体，通过在分子水平上不了解的机制产生新生的HDL。 ABCA1具有两个良好特征的活性，即磷脂酰丝氨酸的外易位，以及其配体ApoA-I的细胞表面结合。我们最近以ABCA1的第三个活性为特征，在AIM 1中展现ApoA-I的N末端螺旋发夹。我们探索了我们的新发现，即磷脂酰肌醇磷酸盐（PIPS）在新生的HDL生物发生中起作用。在AIM 2中，我们探讨了ABCA1在细胞表面部分展开APOA-I的机制，包括我们对ABCA1介导的APOA-I介导的ApoA-I在细胞表面上的酸化的作用。成功完成拟议的研究将提高我们对从头HDL生产机制的了解，这可能会产生对增加HDL生物发生和HDL功能的新策略的见解，并有助于预防CVD。