In some individuals, an elevation in dietary cholesterol intake causes hypercholesterolemia and an increased risk of premature coronary heart disease (CHD). The goal of the present study is to determine specific pathways of dietary cholesterol metabolism that induce atherogenic features of lipoproteins. To accomplish this objective, a nonhuman primate model, the African green monkey, that has many similarities in dietary cholesterol responsiveness to human beings, will be studied. Groups of these animals will be fed low, moderate or high cholesterol containing diets to induce plasma cholesterol concentrations that mimic those of human beings at low, moderate or high risk to increased CHD. Groups will be large enough so that individual animal differences in response to dietary cholesterol can be studied within a group. Diets will be fed for three years to induce atherosclerosis; coronary artery, aortic, and carotid artery atherosclerosis will be quantitated in each of the animals. Periodic measurements of plasma lipids, lipoproteins, and apolipoprotein A-I, B, and E concentrations will be made to document dietary cholesterol effects on each of these endpoints, and heterogeneity in the major lipoprotein classes will be quantitated. Postprandial lipoprotein transport and dietary cholesterol absorption and transport in lymph will be studied in thoracic lymph duct-cannulated animals. Liver biopsys will be taken for determination of apoprotein mRNA abundance and for LDL receptor mRNA abundance, and hepatic LDL receptor protein concentrations will be measured. Finally, liver perfusions will be done to evaluate dietary cholesterol effects on hepatic uptake and secretion of cholesterol-containing lipoproteins and on bile sterol secretion. From these data, we will be able to assess the effect of dietary cholesterol on the pathways of cholesterol movement into and through the liver, and to relate this information to the presence of atherogenic features of lipoproteins in plasma and in lymph. By doing these studies in a primate model of cholesterol metabolism that is relevant to human beings, we will derive information that can be used to develop strategies for prevention of CHD.
