Despite the convincing evidence concerning the relationship between the consumption of saturated fat and levels of plasma LDL cholesterol, the mechanism by which saturated fat induce elevations in LDL cholesterol is not fully understood. Studies of LDL metabolism in both animals and humans suggest that the content of dietary saturate fat affects the clearance rate of LDL by influencing LDL receptor activity. However, the influence of membrane fatty acids on LDL receptor function has not been thoroughly studied; and, in addition, it is possible that alterations in the composition of LDL induced by changes in dietary fat might affect its rate of clearance independent of the amount of receptor present. The overall aim of this study is to understand haw dietary saturated fat influenced LDL metabolism. The hypothesis is that dietary fatty acids influence LDL metabolism both by influencing LDL structure and thus its recognition by the receptor, and also by influencing the composition of cellular fatty acids, thereby influencing the function of the LDL receptor. We have recently developed a stable and sensitive in vitro binding assay system that will allow detection of differences in the kinetics of LDL binding. We will utilize this system to study: 1) how the binding, internalization, and degradation of LDL isolated from primates consuming diets supplemented with various saturated and unsaturated fats may be influenced by diet and 2) the influence on LDL receptor function by cell membranes enriched with various saturated and unsaturated fatty acids. Male cynomolgus macaques will be maintained on diets supplemented with specific fatty acids (palm oil, high stearic fat, high oleic safflower oil, high linoleic safflower oil and menhaden oil) for four week periods. LDL binding will be evaluated as well as detailed measurements of LDL composition including fatty acid composition of LDL subfraction distribution. In the second set of experiments the cell culture medium will be supplemented with known fatty acids similar to those used in the diets. The resultant composition of cell membrane phospholipids will be determined, and binding assays will be conducted using control LDL pools to evaluate whether modifications of cell fatty acids result in changes in receptor function. Through the careful and systematic comparison of the effects of specific fatty acids on LDL binding and receptor function we shall derive information on the mechanism by which changes in dietary fat influence plasma LDL; this will aid in the development of more effective and varied diets for the therapy of hypercholesterolemia.
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| Howard, B V; Hannah, J S; Heiser, C C et al. (1995) Polyunsaturated fatty acids result in greater cholesterol lowering and less triacylglycerol elevation than do monounsaturated fatty acids in a dose-response comparison in a multiracial study group. Am J Clin Nutr 62:392-402 |
