PLASMA LIPID KINETICS IN HYPERCHOLESTROLEMIA

尽管功能性低密度脂蛋白受体的缺陷是 家族性高胆固醇血症的根本缺陷是 由此导致的这些患者的脂代谢变化不是很好。 明白了。这项研究调查了老年人的血浆脂蛋白代谢。 杂合性家族性高胆固醇血症(FH) 假设在FH中，血浆脂质运输系统是由 肝脏胆固醇酯(CE)含量增加 疾病。受试者、正常人和FH患者将被研究 以45%的碳水化合物和40%的脂肪饮食，后者将在 90%碳水化合物饮食会导致极低密度脂蛋白-甘油三酯(TG)升高 分泌和减少肝脏胆固醇的合成。这项实验将 ~3H-亮氨酸、~(14)C-甲戊酸和~3H-甘油的体内示踪 测定其分泌率、滞留时间和血浆转运。 载脂蛋白B(100)、载脂蛋白A1、载脂蛋白A2、CE和TG。测量到的具体情况 这些物质的放射性将由隔室分析 使用SAAM/CONSAM程序进行建模。这项调查将测试四个 特定的机械假说来解释这个已知的反常现象 疾病，如：1.肝脏CE含量增加决定分泌 富含CE而不是TG的apoB颗粒，后者被分泌为 IDL/LDL大小的脂蛋白。2.极低密度脂蛋白-载脂蛋白B在FH中的停留时间为 延长是由于极低密度脂蛋白从血浆中清除减少所致 和它们的残留颗粒，并因为增加了Ce含量 残留物，这损害了它们向IDL和LDL的转化。3.在FH， 富含甘油三酯的极低密度脂蛋白利用率降低成为CETP的速度限制 催化CE/TG转移，从而将CE从高密度脂蛋白转移到 载脂蛋白B。4.从血浆中清除CE不仅仅是通过脂蛋白 通过各种受体介导的机制清除颗粒，但也通过 肝脏CE/TG交换，一种可能的手段，通过它来测定CE含量 在这种疾病中，肝脏变得更大。

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.