Our long term goal is to determine the metabolic and molecular mechanisms by which individuals in a population respond differently to dietary cholesterol and how dietary fat modulates this response. We hypothesize that dietary cholesterol interacts with type of fat in determining plasma lipoprotein variables in a given genetic background. We will test this hytpothesis in selectively bred high and low responding baboons. The first experiment will use a factorial design to determine the interactions of four levels of dietary cholesterol intake, two types of fat (saturated and unsaturated), and two genetic backgrounds (high and low responders) on plasma lipoprotein heterogeneity and concentrations, and on factors in plasma (lecithin cholesterol acyl transferase and cholesteryl ester transfer protein) and liver (mRNA for apoproteins and LDL receptor), that affect plasma lipoprotein concentrations. The second experiment, designed to determine mechanisms accounting for the effects abserved in the first experiment, will use high and low responding baboons maintained on two levels of cholesterol (high and low) with either saturated or unsaturated fat. In these we will measure cholesterol absorption and the synthesis and catabolic rates of apo-B in VLDL, LDL and their subfractions. Turnover rates of apo-AI will be measured to determine whether changes are due to synthesis or catabolism. The HDL metabolic variables and clearance of post-prandial lipoproteins will be correlated with each other and with activities of post-heparin plasma hepatic triglyceride (HTGL) and lipoprotein lipases (LPL) and mRNA for apo-AI and HTGL in liver and LPL in adipose tissues. Apo-E turnover studies will be conducted and the metabolic variables will be correlated with mRNA for apo-E in liver. We will determine whether triglyceride-rich lipoproteins induced by dietary cholesterol promote cholesterol ester synthesis in macrophages. Using primary cultures of baboon hepatocytes, we will study the interaction of chylomicron remnant and fasting lipoproteins with hepatocytes to determine how these lipoproteins affect lipid metabolism in the liver. Using hep G2 cells, we will investigate the down regulation of hepatic LDL receptor by the lipoproteins from high and low responding animals maintained on different diets. These studies will enable us to understand why some indiviuals are susceptible and others resistant to dietary cholesterol.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL041256-01
Application #
3358895
Study Section
(SRC)
Project Start
1988-07-01
Project End
1992-04-30
Budget Start
1988-07-01
Budget End
1989-04-30
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Southwest Foundation for Biomedical Research
Department
Type
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78245
Kushwaha, R S; McGill Jr, H C (1997) Mechanisms controlling lipemic responses to dietary lipids. World Rev Nutr Diet 80:82-125
Kushwaha, R S; Guntupalli, B; Rice, K S et al. (1995) Effect of dietary cholesterol and fat on the expression of hepatic sterol 27-hydroxylase and other hepatic cholesterol-responsive genes in baboons (Papio species). Arterioscler Thromb Vasc Biol 15:1404-11
Kushwaha, R S; Barrett, P H; Reardon, C A et al. (1995) Relationships of plasma and hepatic variables with rates of plasma low-density lipoprotein apolipoprotein B metabolism in baboons fed low- and high-fat diets. Metabolism 44:1058-66
McGill Jr, H C; Kushwaha, R S (1995) Individuality of lipemic responses to diet. Can J Cardiol 11 Suppl G:15G-27G
Kushwaha, R S; Reardon, C A; Getz, G S et al. (1994) Metabolic mechanisms for responses to dietary cholesterol and fat in high and low LDL responding baboons (Papio sp.). J Lipid Res 35:633-43
Kushwaha, R S; Reardon, C A; Lewis, D S et al. (1994) Effect of dietary lipids on plasma activity and hepatic mRNA levels of cholesteryl ester transfer protein in high- and low-responding baboons (Papio species). Metabolism 43:1006-12
Kushwaha, R S; Hasan, S Q; McGill Jr, H C et al. (1993) Characterization of cholesteryl ester transfer protein inhibitor from plasma of baboons (Papio sp.). J Lipid Res 34:1285-97
Hasan, S Q; Kushwaha, R S (1993) Differences in 27-hydroxycholesterol concentrations in plasma and liver of baboons with high and low responses to dietary cholesterol and fat. Biochim Biophys Acta 1182:299-302
Kushwaha, R S; Rice, K S; Lewis, D S et al. (1993) The role of cholesterol absorption and hepatic cholesterol content in high and low responses to dietary cholesterol and fat in pedigreed baboons (Papio species). Metabolism 42:714-22
Kushwaha, R S; McMahan, C A; Mott, G E et al. (1991) Influence of dietary lipids on hepatic mRNA levels of proteins regulating plasma lipoproteins in baboons with high and low levels of large high density lipoproteins. J Lipid Res 32:1929-40

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