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.

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，通过细胞膜蛋白ABCA1充当细胞胆固醇和磷脂的受体，可以通过细胞膜蛋白ABCA1产生新生的HDL，通过在分子水平上不理会的机制。 ABCA1具有几种表征良好的活性，磷脂酰丝氨酸的向外易位以及其配体APOA1的细胞表面结合。在这笔赠款的最后一个周期中，我们表征了ABCA1的两种新活动，即磷脂酰肌醇（4,5）双磷酸（PIP2）的向外易位，该活动是导致APOA1与ABCA1表达细胞结合的，并募集了溶酶体泡量ATPase ATPase（V-ATPase），并促进了Plasane Embrane embrane embrane imbrane imbrane imbrane imbrane empoa poa1的外流易位。 HDL生物发生。在这些发现的基础上，我们建议开发一个无细胞的ABCA1重构系统，从而更好地了解ABCA1组装新生HDL的机制。在AIM 2中，我们探讨了ABCA1将V- ATPase募集到质膜的机制。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。