CAUSES AND TREATMENT OF PRIMARY HYPERCHOLESTEROLEMIA

原发性高胆固醇血症的原因和治疗

• 批准号: 2216410
• 负责人: Scott M. Grundy
• 金额: $ 49.26万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2216410
• 关键词: aging; analytical ultracentrifugation; antihypercholesterolemic agent; antihyperlipoproteinemic agent; apolipoproteins; blood chemistry; blood lipoprotein metabolism; cardiovascular disorder chemotherapy; cardiovascular disorder diagnosis; cardiovascular imaging /visualization; cellular pathology; cerebrotendinous xanthomatosis; cholanate compound; cholesterol; cholesterol ester storage disease; cholestyramine; chylomicrons; clofibrate; combination chemotherapy; coronary disorder; diet therapy; dietary carbohydrates; dietary lipid; disease /disorder proneness /risk; electrofocusing; familial hyperlipoproteinemia; familial hyperlipoproteinemia type II; familial hyperlipoproteinemia type III; feces analysis; fibroblasts; gas chromatography; gel electrophoresis; human population genetics; human subject; hypercholesterolemia; hyperlipidemia; hyperlipoproteinemia; hypertriglyceridemia; immunologic techniques; lecithin cholesterol acyltransferase deficiency; ligands; lipid transport; lipogenesis inhibitor; lipoprotein disorder; lovastatin; low density lipoprotein; macrophage; neomycin; nicotinate; nucleic acid sequence; nutrition related tag; obesity; radiotracer; receptor; reducing diet; sitosterols; steroid metabolism disorder; thin layer chromatography; triglycerides; unsaturated fats; very low density lipoprotein

This proposal will examine the causes of primary hypercholesterolemia (nonfamilial hypercholesterolemia), and it will develop a step-care approach to therapy of this condition. One hundred and sixty patients with primary hypercholesterolemia will be studied. They will first be studied by isotope-kinetic techniques to determine their underlying physiological defect, whether decreased receptor-mediated clearance of LDL, reduced affinity of LDL for receptors, or overproduction of LDL. Family studies will be carried out to determine whether the hypercholesterolemia in some families is inherited as a monogenic disorder. If evidence is obtained for the latter, the underlying metabolic defect will be sought, namely, an abnormality in the primary structure of apolipoprotein B, a reduced ability of cells to generate LDL receptors, an overabsorption of cholesterol, a decreased synthesis of bile acids, or a failure to catabolize saturated fatty acids. In patients with overproduction of LDL, several studies will be done including the composition and lipoprotein content of apolipoprotein E, the interaction of VLDL with cells in culture (fibroblasts and macrophages), and the physical characteristics of LDL. Patients with primary hypercholesterolemia will then enter into a treatment program. The first phase will be diet in which the effectiveness of diets low in fat and high in monounsaturated fats will be compared. The next step will be to study the additional benefit from drugs used in low doses to inhibit the absorption of cholesterol (sitostanol) and bile acids (cholestyramine). Finally, these regimens will be compared to HMG CoA reductase inhibitors (mevinolin). As a last study, the mechanisms of action of mevinolin and cholestyramine will be compared in patients with reduced clearance of LDL, while mevinolin and nicotinic acid will be compared in patients with overproduction of LDL.

该提案将研究主要的原因 高胆固醇血症（非家族性高胆固醇血症） 将开发一种分级护理方法来治疗这种情况。 原发性高胆固醇血症患者一百六十例 将被研究。 首先将通过同位素动力学研究它们 确定其潜在生理缺陷的技术， 受体介导的 LDL 清除率是否降低， LDL 对受体的亲和力，或 LDL 的过量产生。 家庭 将进行研究以确定是否 某些家族的高胆固醇血症是作为单基因遗传的 紊乱。 如果获得了后者的证据，则基础 将寻找代谢缺陷，即代谢异常 载脂蛋白 B 的一级结构，细胞的能力降低 产生低密度脂蛋白受体，胆固醇的过度吸收， 胆汁酸合成减少或分解代谢失败 饱和脂肪酸。 在 LDL 生成过多的患者中， 将进行多项研究，包括组成和 载脂蛋白E的脂蛋白含量与VLDL的相互作用 培养细胞（成纤维细胞和巨噬细胞），以及 低密度脂蛋白的物理特征。 原发性患者 高胆固醇血症将进入治疗计划。 第一阶段是饮食，其中饮食的有效性较低 将比较脂肪含量高和单不饱和脂肪含量高的情况。 这 下一步将是研究所用药物的额外益处 低剂量抑制胆固醇吸收（谷甾烷醇） 和胆汁酸（考来烯胺）。 最后，这些方案将 与 HMG CoA 还原酶抑制剂（mevinolin）相比。 作为最后 研究，mevinolin 和消胆胺的作用机制 将在 LDL 清除率降低的患者中进行比较， 而美维诺林和烟酸将在患者中进行比较 LDL 产生过剩。