LDL METABOLISM

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Currently, there are detailed data available in several rodent species on the mechanisms of regulation of cholesterol synthesis in different organs and the transport mechanisms responsible for plasma low density lipoprotein clearance by these same tissues. Such quantitative data have improved have provided the basis, for the first time, for understanding the nature of the processes that actually regulate circulating plasma LDL-cholesterol levels and have provided the means for exploring the nature of the effects of different diets, exercise and pharmacologic agents on plasma lipid levels. Unfortunately, no such quantitative data are currently available in any primate species. Our studies will measure under in vivo conditions the rates of cholesterol synthesis in all of the major organs of the Cynomolgus monkey under circumstances of low and high dietary cholestrol intake in both "responding" and "nonresponding" animals. Furthermore, using a newly developed steady-state infusion technique, absolute rates of both receptor-dependent and receptor-independent low density lipoprotein transport will be quantitated in each of these same organs. Regulations of both rates of cholesterol synthesis and LDL transport will be investigated in other studies under circumstances where there has been an alteration in the diet (cholesterol content or degree of saturation of the long-chain fatty acids) or where there is a difference in the genetic background of the animals. This latter group of studies will be particularly important (relative to human LDL physiology) since groups of these monkeys have been defined which respond adversely to increased dietary cholesterol by markedly elevating their circulating plasma cholesterol levels. These studies should provide the first quantitative in vivo data on the mechanisms of regulation of cholesterol synthesis and low density lipoprotein transport in the major organs of this primate species, and these data should provide the means for the preliminary mathematical modeling of LDL turnover in the primate. If these preliminary studies are successful, it will open the way for the more extensive use of this species in the study of LDL metabolism in the primate.