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.
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