The Role of ABCA1 in HDL Subfraction Formation

高密度脂蛋白(HDL)的浓度与罹患糖尿病的风险呈负相关。 早发性冠心病，但我们对代谢途径的理解- 特罗尔血浆高密度脂蛋白浓度是有限的。高密度脂蛋白以离散大小的亚组分存在于血浆中 可按载脂蛋白含量和大小分为小颗粒、中颗粒和大颗粒。 每个颗粒含有两个、三个和四个载脂蛋白A-I(载脂蛋白A-L)。的总目标是 本项目旨在阐明高密度脂蛋白亚组分形成的分子途径，以填补 了解控制血浆高密度脂蛋白浓度和高密度脂蛋白亚组分异质性的因素。 我们以前的研究和初步数据描述了一种新的高密度脂蛋白亚组分Me的途径-- 非人灵长类动物和人apoA-I转基因小鼠体内的代谢 在从血浆中移除之前以单向路径垂直到中等或大型高密度脂蛋白 被肝脏分解代谢的。此外，我们的数据显示没有证据表明前贝塔病毒的产生。 大密度脂蛋白分解代谢过程中的载脂蛋白A-I。在下一个拨款周期中，我们建议调查 利用转基因和基因靶向小鼠研究高密度脂蛋白亚组分代谢的分子途径 阐明高密度脂蛋白亚组分颗粒组装、血管内代谢和 组织分解代谢。在特定的目标1中，我们将检验肝脏和肠道是 利用肝脏和肠道特异性ABCA1转运蛋白组装新生高密度脂蛋白的主要部位 基因敲除老鼠。在特定的目标2中，我们将检验肝脏ABCA1功能的假设 限制无脂载脂蛋白A-I与脂类的组装形成新生的盘状小高密度脂蛋白颗粒。 在特定的目标3中，我们将测试ABCA1参与将脂质添加到小分子的假设 球形血浆高密度脂蛋白及其向外界中大颗粒的转化 电浆舱。这些拟议研究的结果将增加我们在以下方面的基本能力： 了解AbcAl在高密度脂蛋白亚组分形成和成熟中的作用，并可能导致 更好地了解提高血浆高密度脂蛋白浓度或刺激反向胆固醇的方法- 叔醇通过饮食或药物方法运输。

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.