LIPID DETERMINANTS OF HIGH DENSITY LIPOPROTEIN (HDL) STRUCTURE

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High density lipoprotein (HDL) concentrations are inversely associated with coronary heart disease in human and nonhuman primates. We propose to use two species of nonhuman primates, the hyper-responding cynomolgus monkey and the hypo-responding African green monkey, which exhibit low vs. high plasma HDL concentrations, respectively, to study the diet- induced changes in the biophysical properties of HDL which result in altered concentration and distribution of plasma HDL subfractions. In both species n-3 and n-6 polyunsaturated dietary fat reduces HDL concentrations relative to saturated fat. In addition, the type of dietary fat has opposing effects on HDL subfraction distribution in African green monkeys; relative to saturated fat, n-6 polyunsaturated dietary fat raises and n-3 polyunsaturated fat lowers HDL subfractions of intermediate size and density. We hypothesize that the biophysical properties of the lipid surface on nascent HDL particles modulates the size distribution and concentration of plasma HDL subfractions through effects on apoprotein binding and conformation and on LCAT maturation of nascent HDL to mature plasma HDL. These biophysical properties include affinity and capacity for apoprotein conformation, lipid fluidity and lecithin:cholesterol acyltransferase (LCAT) reactivity. We will test our hypothesis by first defining the diet-induced changes in the biophysical properties of plasma and liver perfusate HDL derived from both species of monkeys fed 4 types of dietary fat. The different types of dietary fat will allow us to modify the concentration, composition, and subfraction distribution of plasma and liver perfusate HDL in 2 species of monkeys that have contrasting levels of plasma HDL. We will then study the LCAT-induced maturation of liver perfusate HDL to mature plasma HDL to define the important biophysical properties of liver perfusate HDL that result in the diet-induced changes in plasma HDL concentration, composition, and subfraction distribution. Recombinant HDL (rHDL) will be made which mimic the size and composition of liver perfusate HDL and will be used as chemically-defined surrogates of liver perfusate HDL. The LCAT induced-maturation of RHDL to spherical "plasma like" HDL will be studied and compared with results from similar studies with liver perfusate HDL to elucidate key biophysical properties which affect HDL particle heterogeneity. Finally, monolayer studies will be used to define specific surface properties which affect apoprotein binding and conformation on HDL and may contribute to the observed HDL particle heterogeneity. The results from this project should lead to new and important information regarding the biophysical aspects of HDL particle structure which affect HDL particle heterogeneity. In addition, we will learn how the type of dietary fat fed to nonhuman primates influences the biophysical properties of plasma and liver perfusate HDL and the maturation of nascent liver HDL to mature plasma HDL. The results from this study should lead to a better understanding of HDL metabolism and could be used to make more national decisions concerning dietary treatment of individuals at risk for coronary heart disease.