Elevated concentrations of plasma low density lipoproteins (LDL) are implicated in the pathogenesis of atherosclerosis. The liver plays an important role in the regulation of plasma LDL concentrations since Greater Than 50% of LDL catabolism occurs in this organ (at least in the hamster and rat). In the proposed studies hamsters and rats will be subjected to a variety of dietary, pharmacologic and hormonal manipulations which are known to alter LDL concentrations. Using a constant infusion technique recently developed in this lab, rates of hepatic [14C]sucrose-LDL uptake will be measured in groups of treated and control animals. Aliquots of liver from each of these animals will also be used for the determination of sterol synthesis using [3H]water in vitro and for the determination of free and esterified cholesterol concentrations so that the relationship among rate of LDL uptake, rate of sterol synthesis and size of the cholesterol ester pool will be obtained in each animal. Rates of whole-animal [14C]sucrose-LDL clearance and rates of hepatic and whole-animal sterol synthesis using [3H]water in vivo will then be measured in separate groups of treated and control animals. Thus, these studies will help to define the relationship among rates of LDL uptake, rates of sterol synthesis and size of the cholesterol ester pool in the maintenance of cholesterol homeostasis in the intact liver. They will also give information on the mechanisms by which LDL concentrations are altered in several clinically important situations including: 1) bile acid feeding, 2) cholesterol feeding, 3) therapy with hypocholesterolemic drugs, 4) fasting, 5) aging and 6) endocrine disturbances.
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