The Role of ABCA1 in HDL Subfraction Formation

ABCA1 在 HDL 亚组分形成中的作用

• 批准号: 7450736
• 负责人: JOHN E PARKS
• 金额: $ 35.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7450736
• 关键词: ATP-Binding Cassette Transporters; Agonist; Albumins; Animals; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Apolipoproteins A; Biliary; Catabolism; Cell Line; Cellobiose; Cells; Charge; Cholesterol; Complementary DNA; Confounding Factors (Epidemiology); Coronary heart disease; Culture Media; Cultured Cells; Data; Development; Diet; Ethers; Ethyl Ether; Event; Excretory function; Gel; Gene Targeting; Generations; Goals; Grant; Hepatic; Hepatocyte; Heterogeneity; High Density Lipoproteins; Human; In Vitro; Intestines; Knockout Mice; Knowledge; Lead; Lipids; Lipoprotein (a); Lipoprotein (a-); Lipoproteins; Liver; Measures; Membrane Transport Proteins; Metabolic; Metabolic Clearance Rate; Metabolic Pathway; Metabolism; Methods; Mining; Molecular; Molecular Sieve Chromatography; Monitor; Mus; Particle Size; Pathway interactions; Peripheral; Phospholipids; Plasma; Population Heterogeneity; Positioning Attribute; Process; Production; Radiolabeled; Rate; Risk; Role; Sepharose; Site; Testing; Time; Tissues; Transfection; Transgenic Mice; Transgenic Organisms; Tyramine; Up-Regulation; Wild Type Mouse; base; denaturing gradient gel electrophoresis; density; macrophage; nonhuman primate; novel; particle; pre-beta high-density lipoprotein; protective effect; radiotracer; receptor; residence; reverse cholesterol transport; saturated fat; size; uptake

The concentration of high density lipoproteins (HDLs) is inversely associated with the risk of devel- oping premature coronary heart disease, but our understanding of the metabolic pathways that con- trol plasma HDL concentrations is limited. HDLs exist in plasma as discrete size subfractions that can be separated by apolipoprotein content and size into small, medium, and large particles con- taining two, three, and four molecules of apolipoprotein A-I (apoA-l) per particle. The overall goal of this project is to elucidate the molecular pathways of HDL subfraction formation to fill the gaps in knowledge of factors that control plasma concentrations of HDL and HDL subfraction heterogeneity. Our previous studies and preliminary data have described a novel pathway for HDL subfraction me- tabolism in non-human primates and in human apoA-I transgenic mice in which small HDL are con- verted in a unidirectional pathway to medium or large HDL before being removed from plasma and catabolized by the liver. Furthermore, our data show no evidence for the production of pre-beta apoA-I during the catabolism of large HDL. In the next grant cycle, we propose to investigate the molecular pathways of HDL subfraction metabolism using transgenic and gene targeted mice to elucidate the molecular details of HDL subfraction particle assembly, intravascular metabolism, and tissue catabolism. In Specific aim 1, we will test the hypothesis that the liver and intestine are the major sites of nascent HDL assembly using hepatic and intestinal specific AbcA1 transporter knockout mice. In Specific aim 2, we will test the hypothesis that hepatic AbcA1 function is rate limiting in the assembly of lipid free apoA-I with lipid to form small nascent discoidal HDL particles. In Specific aim 3, we will test the hypothesis that AbcA1 is involved in the addition of lipid to small spherical plasma HDL and their subsequent conversion to medium and large HDL particles outside the plasma compartment. The results of these proposed studies will increase our basic under- standing of the role of AbcAl in the formation and maturation of HDL subfractions and may lead to a better understanding of ways to increase plasma HDL concentrations or stimulate reverse choles- terol transport by dietary or pharmacological methods.

高密度脂蛋白（HDL）的浓度与发育风险呈负相关。 但我们对代谢途径的理解， 控制血浆HDL浓度是有限的。HDL在血浆中以离散大小的亚组分存在， 可以通过载脂蛋白含量和大小分为小、中、大颗粒， 每个颗粒含有两个、三个和四个载脂蛋白A-I（apoA-I）分子。的总目标 本项目旨在阐明HDL亚组分形成的分子途径，以填补 了解控制HDL血浆浓度和HDL亚组分异质性的因素。 我们先前的研究和初步数据描述了HDL亚组分代谢的一种新途径， 在非人灵长类动物和人apoA-I转基因小鼠中， 在从血浆中去除之前，在单向途径中转化为中等或大HDL， 被肝脏分解代谢此外，我们的数据显示，没有证据表明生产前β apoA-I在大HDL代谢中的作用。在下一个资助周期，我们建议调查 使用转基因和基因靶向小鼠研究HDL亚组分代谢的分子途径， 阐明HDL亚组分颗粒组装、血管内代谢的分子细节， 组织卡他赛在具体目标1中，我们将检验肝和肠是肠道的假设。 使用肝和肠特异性AbcA 1转运蛋白的新生HDL组装的主要位点 敲除小鼠在具体目标2中，我们将检验肝脏AbcA 1功能是速率的假设。 限制无脂质apoA-I与脂质组装形成小的新生盘状HDL颗粒。 在具体目标3中，我们将检验AbcA 1参与向小细胞添加脂质的假设。 球形血浆HDL及其随后转化为外部的中等和大HDL颗粒 血浆舱这些建议的研究结果将增加我们的基本下- AbcAl在HDL亚组分的形成和成熟中的作用，并可能导致 更好地了解增加血浆HDL浓度或刺激逆转胆固醇的方法- 通过饮食或药理学方法转运固醇。