Monosaccharides and disaccharides are known to result in hyperlipoproteinemia in rabbit nutritional studies. In rabbits fed semi-purified diets, sucrose as a carbohydrate source results in hyperlipoproteinemia in excess of that of dietary glucose or fructose. In the sucrose model significant hypercholesterolemia and hypertriglyceridemia occur followed by early atherosclerotic changes in ten to twenty weeks. In these rabbits the hyperlipoproteinemia is of endogenous origin as marked by the apo B variant, apo BH, of hepatic origin. Full characterization in the rabbit model of hyperlipoproteinemia in the absence of exogenous cholesterol is important considering proposals to substitute carbohydrate for fat in human diets. We propose to study effects of dietary sucrose or constituent monosaccharides, fructose or glucose on plasma lipoproteins over a twenty week period including tolerance of sugars following acute administration. In vivo studies will be complemented by rabbit hepatocyte studies of lipoprotein synthesis and secretion using radionuclide incorporation studies of lipids, apolipoproteins, and phosphorylated forms of apo B. Primary hepatocyte studies will characterize the acute regulation by insulin of lipoprotein synthesis and secretion using media containing fructose and/or glucose, fatty acids and various hormones (glucagon and dexamethasone). The effect of insulin on degree of apo B phosphorylation will be studied. These studies will further previous hepatocyte experiments in a model where only apo BH is secreted. Monoclonal antibodies to rabbit apolipoproteins will be used in the quantitation of apolipoproteins, immunoaffinity isolation of subpopulations of lipoproteins and immunochemical identification of lipoproteins that contain multiple epitopes. Particle composition of various lipoprotein fractions with respect to lipids and apolipoprotein composition and particle heterogeneity will be determined by epitope specific immunoaffinity isolation. The rabbit model is important to develop as it closely approximates the human in terms of endogenous apo B secretion and its ability to be studied in terms of atherogenesis. Particle composition of apo B and apo A-I lipoproteins is seen as critical to the cholesterol balance in the arterial wall and particle composition is well known to be critical in hepatic and peripheral clearance of lipoproteins. Studies are important considering apo B and apo A-I lipoproteins are risk factors in atherogenesis.
