ABCA1, ApoAI and Reverse Cholesterol Transport

高密度脂蛋白(高密度脂蛋白)-胆固醇水平高与心血管疾病风险降低有关。虽然高密度脂蛋白的保护作用可能有几种机制，但高密度脂蛋白和高密度脂蛋白的主要蛋白质成分载脂蛋白AI(ApoA1)是胆固醇反向运输途径的主要组成部分，在这一途径中，胆固醇从外周清除并转移到肝脏排泄。在胆固醇反向运输途径的第一步，apoA1通过细胞膜蛋白ABCA1作为细胞胆固醇和磷脂的受体，产生新生的高密度脂蛋白。 尽管该途径中的这一步正在进行深入的研究，但我们仍然对ABCA1介导的细胞脂质在ApoAI上组装的分子细节知之甚少。并不是所有的高密度脂蛋白都是等同的，有几项研究报告说，冠心病患者的高密度脂蛋白功能障碍。我们最近创造了一种apoA1变体，它可以抵抗功能失调。我们建议在两个特定的目标下跟踪载脂蛋白A1脂化和胆固醇反向转运的机制。目标1将使用生物物理、生化和遗传方法解决载脂蛋白A1的无细胞和细胞脂肪作用的机制。目的2将阐述载脂蛋白A1修饰在体内胆固醇反向运输和动脉粥样硬化病变消退中的作用。我们将探索炎症对胆固醇反向运输和apoA1修饰的影响，并将确定我们的新apoA1变异体在介导几种小鼠模型中的胆固醇反向运输和病变消退方面是否优于野生型apoA1。换句话说，我们希望我们的发现能让我们的“好胆固醇”变得更好。

High levels of high density lipoprotein (HDL)-cholesterol are associated with lowered risk for cardiovascular disease. Although several mechanisms may play a role in HDL's protective effect, HDL and apolipoprotein-AI (apoAl), the major protein constituent of HDL, are major components of the reverse cholesterol transport pathway, in which cholesterol is removed from the periphery and transferred to the liver for excretion. In the first step of the reverse cholesterol transport pathway, apoAl acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCAl, generating nascent HDL. Although this step in the pathway has been under intensive investigation, we still know very little about the molecular details of the ABCAl mediated assembly of cellular lipids on apoAI. Not all HDL is equivalent, and several studies have reported that individuals with coronary artery disease have HDL that is dysfunctional. We recently created an apoAl variant that is resistant to becoming dysfunctional. We propose to follow up on the mechanism of apoAl lipidation and reverse cholesterol transport in two specific aims. Aim 1 will address mechanisms of both cell-free and cellular lipidation of apoAl using biophysical, biochemical, and genetic approaches. Aim 2 will address the role of apoAl modification on in vivo reverse cholesterol transport and atherosclerosis lesion regression. We will explore the effects of inflammation on reverse cholesterol transport and apoAl modification, and we will determine if our novel apoAl variant is superior to wild type apoAl in mediating reverse cholesterol transport and lesion regression in several mouse models. In other words, we hope the discoveries we make will allow us to make "good cholesterol" even better.