PLASMA LIPID KINETICS IN HYPERCHOLESTROLEMIA

高胆固醇血症的血浆脂质动力学

• 批准号: 3340489
• 负责人: WALDO R FISHER
• 金额: $ 27.27万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3340489
• 关键词: antihypercholesterolemic agent; apolipoproteins; blood lipoprotein metabolism; blood lipoprotein transport; carbon; cholesterol esters; clearance rate; dietary carbohydrates; familial hyperlipoproteinemia type II; fluorimetry; gel electrophoresis; high density lipoproteins; human subject; leucine; lipid metabolism; lipid transport; liver metabolism; low density lipoprotein; mevalonate; molecular pathology; nutrition related tag; phosphatidylcholines; radionuclide diagnosis; radionuclides; radiotracer; secretion; secretory protein; triglycerides; tritium; very low density lipoprotein

Though the deficiency of a functional low density lipoprotein receptor is the fundamental defect in the disease familial hypercholesterolemia, the resultant alterations in lipid metabolism in these patients are not well understood. This research investigates plasma lipoprotein metabolism in heterozygous familial hypercholesterolemia (FH) and builds upon the general hypothesis that in FH the plasma lipid transport system is driven by the increased hepatic cholesterol ester (CE) content which occurs in this disease. Human subjects, normal controls and FH patients, will be studied on a 45% carbohydrate, 40% fat diet, and the latter will be restudied on a 90% carbohydrate diet which will induce increased VLDL-triglyceride (TG) secretion and decreased hepatic cholesterol synthesis. The experiment will utilize in vivo tracers of 3H-leucine, 14C-mevalonatic acid and 3H-glycerol to measure the secretory rates, residence times and plasma transports of apolipoprotein B(100), apoA1, apoA2, CE and TG. The measured specific radioactivity of these substances will be analyzed by compartmental modeling using the SAAM/CONSAM program. The investigation will test four specific mechanistic hypotheses to explain known abnormalities in this disease, as follows: 1. Increased hepatic CE content determines secretion of apoB particles enriched in CE rather than TG, which are secreted as IDL/LDL sized lipoproteins. 2. The residence time of VLDL-apoB in FH is prolonged both as a consequence of reduced clearance from plasma of VLDL and their remnant particles and because of increased CE content of the remnants, which impairs their conversion to IDL and LDL. 3. In FH, decreased availability of TG-enriched VLDL becomes rate limiting for CETP catalyzed CE/TG transfer, thus reducing the transfer rate of CE from HDL to apoB. 4. The removal of CE from plasma occurs not only by lipoprotein particle clearance through various receptor mediated mechanisms but also by hepatic CE/TG exchange, a possible means by which the CE content of the liver becomes increased in this disease.

虽然功能性低密度脂蛋白受体的缺乏是 家族性高胆固醇血症的根本缺陷是， 这些患者的脂质代谢的结果改变并不好 明白 本研究探讨了血浆脂蛋白代谢， 杂合子家族性高胆固醇血症（FH），并建立在一般 假设在FH中，血浆脂质转运系统由 肝胆固醇酯（CE）含量增加， 疾病 将研究人类受试者、正常对照和FH患者 45%碳水化合物，40%脂肪饮食，后者将在 90%碳水化合物饮食，将诱导VLDL-甘油三酯（TG）升高 分泌和降低肝胆固醇合成。 实验将 利用3H-亮氨酸、14C-甲羟戊酸和3H-甘油的体内示踪剂 以测量的分泌率，停留时间和血浆运输的 载脂蛋白B（100）、apoA1、apoA2、CE和TG。 测得的特异性 这些物质的放射性将通过隔室分析进行分析 使用SAAM/CONSAM程序建模。 调查将测试四个 特定的机制假说来解释已知的异常， 疾病，如下：1。肝CE含量增加决定分泌 富含CE而不是TG的apoB颗粒，其分泌为 IDL/LDL大小的脂蛋白。 2. VLDL-apoB在FH中的停留时间为 由于血浆中VLDL清除率降低， 以及它们的残余颗粒，并且由于 残余物，这损害了它们向IDL和LDL的转化。 3.在FH中， TG富集的VLDL的可用性降低成为CETP的速率限制 催化CE/TG转移，从而降低CE从HDL到TG的转移速率。 apoB. 4. CE从血浆中的去除不仅通过脂蛋白 颗粒清除通过各种受体介导的机制，但也通过 肝CE/TG交换，一种可能的方法，通过这种方法， 肝脏在这种疾病中变得更大。