REVERSE CHOLESTEROL TRANSPORT IN DIABETES

动脉粥样硬化是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 部分是由于HDL介导的胆固醇逆向转运受损， 糖尿病，导致细胞中过量胆固醇的积累， 动脉壁 最近的研究表明，去除胆固醇， 组织是由脂质贫载脂蛋白介导， 总HDL颗粒群的组分。 这一目标 他们的建议是测试胰岛素依赖型糖尿病如何影响 HDL颗粒和脂质贫乏的载脂蛋白， 细胞以及糖尿病相关分子如何在细胞中积累， 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，组成， 胰岛素依赖型糖尿病患者HDL 1颗粒的物理性质 受试者;以确定葡萄糖诱导的HDL修饰 载脂蛋白损害HDL颗粒从细胞中除去脂质的能力， 细胞;并测试糖尿病相关分子的调节作用 对动脉平滑肌细胞和巨噬细胞的脂质流出的影响。 将进行实验以比较血清和 来自糖尿病和正常受试者的血浆在去除胆固醇和 在体外和体内HDL颗粒的磷脂糖基氧化减少 它们的脂质去除活性;并且为了检查胰岛素的能力， TNF-α糖化和糖氧化蛋白以及巨噬细胞衍生的载脂蛋白 E来调节培养的小鼠的胆固醇和磷脂排泄 动脉平滑肌细胞和巨噬细胞。这些研究将提供 对糖尿病状态的可能机制的重要见解 抑制动脉细胞中多余胆固醇的流动 并增强动脉粥样硬化形成。

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.