DIETARY FATTY ACIDS EFFECT ON LIPOPROTEIN TRANSPORT

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Plasma levels of low density lipoprotein (LDL) and high density lipoprotein (HDL) are two of the factors considered most important in the genesis of atherosclerosis and coronary heart disease (CHD). The long-term goal of the proposed studies is to understand how dietary lipids, in particular saturated and unsaturated fatty acids, regulate plasma concentrations of LDL and HDL. The significance of the project is emphasized by the high prevalence of CHD, the extraordinary cost of treatment and the potential for prevention by dietary intervention. Utilizing the hamster as an animal model whose response to diet modification is similar to humans, we have shown that dietary lipids alter plasma LDL concentrations primarily by regulating receptor-dependent LDL uptake by the liver. Using quantitative techniques to measure lipoprotein transport and gene expression, one group of studies will determine the mechanisms whereby the major fatty acids present in western diets regulate receptor-dependent LDL uptake by the liver. The effect of chain-length on saturated fatty acid-induced alterations in LDL receptor gene expression will also be examined. We recently showed that changes in LDL receptor mRNA levels account for changes in hepatic LDL receptor activity when dietary coconut oil is replaced by safflower oil. If the major fatty acids present i n western diets are shown to regulate hepatic LDL receptor activity at the transcriptional level, the promoter sequences involved will be determined using adenovirus mediated transfer of LDL receptor promoter/reporter constructs into the liver in vivo. A second-group of studies will be undertaken to understand how specific components of the diet regulate plasma HDL concentrations in the hamster and, in turn, to determine if diet-induced changes in plasma HDL levels reflect changes in the rate of reverse cholesterol transport. The saturation kinetics of HDL apo AI transport will first be established in vivo. Having established the kinetics of HDL transport, studies will be undertaken to determine how specific dietary components regulate HDL apo AI and cholesteryl ester levels. Finally, studies will be carried out to investigate the relationship between diet-induced changes in plasma HDL concentrations and the flux of HDL cholesterol back to the liver and to determine if primary overexpression of apo AI results in mobilization of cholesterol from peripheral tissues and enhanced reverse cholesterol transport. Overall, these detailed quantitative studies will provide important new information on the molecular mechanisms whereby specific dietary components regulate the major transport processes that control plasma LDL and HDL levels.