ApoA1 lipidation by ABCA1 in HDL biogenesis

HDL 生物合成中 ABCA1 对 ApoA1 脂化

基本信息

批准号：
10206232
负责人：
Jonathan D Smith
金额：
$ 47.95万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206232
关键词：
ATP binding cassette transporter 1 Apolipoprotein A-I Apolipoproteins Apolipoproteins B Area Atherosclerosis Binding Biochemical Biogenesis Biological Assay Biological Markers Biology Cardiovascular Diseases Cell Membrane Proteins Cell membrane Cell surface Cells Cholesterol Consensus Coronary heart disease Data Detergents Drops Endothelium Environment Excretory function Extracellular Domain Future Generations Genes Genetic Grant High Density Lipoprotein Cholesterol High Density Lipoproteins Human Intestines Knowledge LDL Cholesterol Lipoproteins Lead Ligands Lipids Lipoproteins Liposomes Liver Logistic Regressions Measures Mediating Membrane Mendelian randomization Molecular Mutagenesis Observational Study Pathway interactions Peripheral Pharmaceutical Preparations Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphatidylserines Phospholipids Plasma Play Predisposition Process Production Prospective Studies Proteins Proton Pump RNA Reaction Reporting Research Research Design Role Steroid biosynthesis Structure System Tangier Disease Tertiary Protein Structure Testing Therapeutic Tissues Transgenic Mice Triglycerides cardiovascular disorder prevention cardiovascular disorder risk epidemiology study genetic variant immunoregulation inorganic phosphate insight lipid metabolism membrane activity mouse model novel particle population based prevent protective effect protein protein interaction reconstitution recruit reverse cholesterol transport tumor progression vacuolar H+-ATPase

项目摘要

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-AI (apoA1), are critical components of this process. In the first step of the RCT pathway, lipid-poor apoA1 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 several well characterized activities, the outward translocation of phosphatidylserine, and the cell surface binding of its ligand apoA1. In the last cycle of this grant we characterized two novel activities of ABCA1, the outward translocation of phosphatidylinositol (4,5) bis-phosphate (PIP2) that is responsible for apoA1 binding to ABCA1 expressing cells, and the recruitment of the lysosomal vacuolar ATPase (V-ATPase) to the plasma membrane leading to local acidification of apoA1 that promotes its unfolding and HDL biogenesis. Building on these discoveries we propose to develop a cell-free ABCA1 reconstituted system, allowing a better understanding of the mechanism by which ABCA1 assembles nascent HDL. In Aim 2, we explore the mechanism by which ABCA1 recruits V- ATPase to the plasma membrane. 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.

流行病学研究表明，高密度脂蛋白胆固醇 (HDL-C) 水平与心血管疾病 (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-AI (apoA1) 是该过程的关键组成部分。在 RCT 途径的第一步中，贫脂 apoA1 通过细胞膜蛋白 ABCA1 作为细胞胆固醇和磷脂的受体，通过分子水平上尚不了解的机制生成新生 HDL。 ABCA1 具有多种明确的活性，包括磷脂酰丝氨酸的向外易位及其配体 apoA1 的细胞表面结合。在本次资助的最后一个周期中，我们描述了 ABCA1 的两种新活性，即负责 apoA1 与 ABCA1 表达细胞结合的磷脂酰肌醇 (4,5) 二磷酸 (PIP2) 的向外易位，以及溶酶体液泡 ATP 酶的募集(V-ATPase) 到达质膜，导致 apoA1 局部酸化，促进其解折叠和 HDL 生物发生。基于这些发现，我们建议开发一种无细胞 ABCA1 重组系统，以便更好地了解 ABCA1 组装新生 HDL 的机制。在目标 2 中，我们探索了 ABCA1 将 V-ATP 酶招募到质膜的机制。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。