REVERSE CHOLESTEROL TRANSPORT IN DIABETES

动脉粥样硬化是两种疾病发病率和死亡率的主要原因。 胰岛素依赖型和非胰岛素依赖型糖尿病。这可能会出现在 部分原因是高密度脂蛋白介导的胆固醇反向转运受损 糖尿病，导致过多的胆固醇在细胞内积聚 动脉壁。最近的研究表明，从 组织是由少量的低脂载脂蛋白调节的。 高密度脂蛋白颗粒总数的组成部分。这样做的目的是 是为了测试胰岛素依赖型糖尿病是如何影响 高密度脂蛋白颗粒和低脂载脂蛋白的作用 细胞以及与糖尿病相关的分子是如何在 动脉壁影响动脉细胞中胆固醇的排泄途径。 建议进行研究，以检查功能、成分和 胰岛素依赖型糖尿病患者高密度脂蛋白颗粒的物理性质 受试者；以确定葡萄糖是否诱导高密度脂蛋白的改变 载脂蛋白削弱高密度脂蛋白颗粒去除脂质的能力 细胞；并测试糖尿病相关分子的调节作用 动脉平滑肌细胞和巨噬细胞的脂质外流。 将进行实验，以比较血清和 糖尿病患者和正常人血浆对胆固醇的清除作用 体内和体外高密度脂蛋白颗粒的磷脂糖氧化减少 它们的去脂活性；并检查胰岛素的能力， 肿瘤坏死因子-α糖化和糖化蛋白与巨噬细胞源性载脂蛋白 调节培养细胞胆固醇和磷脂的排泄 动脉平滑肌细胞和巨噬细胞。这些研究将提供 对糖尿病状态可能的机制的重要见解 抑制动脉细胞中过量胆固醇的动员 并增强动脉粥样硬化的形成。

Atherosclerosis is the major cause of morbidity and mortality in both insulin-dependent and insulin-independent diabetes. This may arise in part by an impaired HDL-mediated reverse cholesterol transport in diabetes, leading to accumulation of excess cholesterol in cells of the artery wall. Recent studies suggest that the removal of cholesterol from tissues is mediated by lipid poor apolipoproteins that are minor components of the total HDL particle population. The objectives of this proposal are to test how insulin-dependent diabetes affects the ability of HDL particles and lipid-poor apolipoproteins to remove lipids from cells and how diabetes-relevant molecules that may accumulate in the artery wall influence cholesterol excretory pathways in arterial cells. Studies are proposed to examine the functional, compositional, and physical properties of HDLl particles in insulin-dependent diabetic subjects; to determine if glucose-induced modifications of HDL apolipoproteins impair the ability of HDL particles to remove lipids from cells; and to test the regulatory effects of diabetes-relevant molecules on lipid efflux from a arterial smooth muscles cells and macrophages. Experiments will be conducted to compare the activities of serum and plasma from diabetic and normal subjects in removing cholesterol and phospholipid glycoxidation of HDL particles in vitro and in vivo reduces their lipid removal activities; and to examine the ability of insulin, TNF-alpha glycated and glycoxidated proteins, and macrophage derived apo E to modulate cholesterol and phospholipid excretion from cultured arterial smooth muscles cells and macrophages. These studies will provide important insights into possible mechanisms by which the diabetic state suppresses mobilization of excess cholesterol from cells of the artery wall and enhances atherogenesis.