REGULATION OF PLASMA CHOLESTEROL METABOLISM

我们观察到细胞与血浆之间持续的代谢缺陷。 胆固醇在几类人体内的转运。这些节目展示了 主要脂蛋白浓度或组成没有共同特征，但 都是动脉粥样硬化性血管疾病的高危人群。对…的抑制 胆固醇酯转移与载脂蛋白原的发生有关 绕过卵磷脂的E依赖分流途径：胆固醇酰基转移酶 (LCAT)。受影响的群体包括熟悉的 高胆固醇血症，非胰岛素依赖型糖尿病患者，以及 与记录在案的血管疾病相关的常见高甘油三酯血症 还有早衰症。在这项提案中，我们想要确定这是否 代谢异常在其他糖尿病患者群体中也存在。我们会 测定各组分的反应速率和反应物浓度 细胞-血浆胆固醇转运梯度(胆固醇携带者 脂蛋白；卵磷脂：胆固醇酰基转移酶；胆固醇酯 未经治疗的糖尿病患者，以及血糖和 胰岛素改善了代谢控制，使血脂正常化。 此外，还研究了该化合物的结构、组成和代谢作用 糖尿病受体脂蛋白，治疗前和正常血糖后， 将会被研究。载脂蛋白E分流脂蛋白的组成 组分将用免疫亲和层析进行研究。使用特定的 抗脂蛋白载脂蛋白的固定化抗体，化学计量学和 这一组分的浓度将被确定。结合的脂蛋白将 使用新开发的温和解吸技术进行分离以进行进一步分析 技巧。最后我们将研究糖尿病血细胞在多大程度上 而血小板可能会以与其能力相关的方式进行修饰 促进胆固醇转运。可能存在特定的涌入 载脂蛋白E转运的游离胆固醇的位置将被检测。这个 胰岛素代谢调控对胆固醇转运的正常化作用 糖尿病患者提供了一个研究这种缺陷的机制的机会。 脂类代谢。这些结果似乎与基本的 人体动脉粥样硬化形成的生物化学。

We have observed a consistent metabolic defect in cell-to-plasma cholesterol transport in several categories of human subject. These show no common feature of major lipoprotein concentration or composition but are all at high risk for atherosclerotic vascular disease. An inhibition of cholesteryl ester transfer is associated with development of an apo E-dependent shunt pathway bypassing lecithin: cholesterol acyltransferase (LCAT). Affected groups include patients with familiar hypercholesterolemia, non-insulin-dependent diabetics, and those with familiar hypertriglyceridemia associated with documented vascular disease and progeria. In this proposal we would like to determine whether this metabolic abnormality is also shared by other groups of diabetics. We will assay the reaction rates and reactant concentrations of components of the cell-to-plasma cholesterol transport gradient (cholesterol carrier lipoprotein; lecithin:cholesterol acyltransferase; cholesteryl ester transfer) in untreated diabetics, and diabetics whose plasma glucose and lipids are normalized with improved metabolic control with insulin. Additionally the structure, composition and metabolic interations of the diabetic acceptor lipoproteins, before treatment and after normoglycemia, will be studied. The composition of the apo E-containing shunt lipoprotein fraction will be studied by immunoaffinity chromatography. Using specific immobolized antibodies to lipoprotein apoproteins, the stoichiometry and concentration of this fraction will be determined. Bound lipoproteins will be separated for further analysis using newly developed mild desorption techniques. Finally we will study the extent to which diabetic blood cells and platelets may be modified in ways that relate to their ability to promote cholesterol transport. The possible existence of specific influx sites for apo E-transported free cholesterol will be assayed. The normalization of cholesterol transport by metabolic control with insulin in diabetics offers an opportunity to study the mechanism of this defect of lipid metabolism. The results appear to have major relevance to the basic biochemistry of atherogenesis in human subjects.