Lawrence L. Rudel, PhD
Cholesterol Metabolism, Lipoproteins, Primates
Complications arising from coronary heart disease are the number one cause of death in our country. Atherosclerosis is the underlying disease process. We have developed nonhuman primate (monkey) models of diet-induced coronary artery atherosclerosis (CAA). We are attempting to define molecular mechanisms through which dietary fatty acids modify plasma lipoprotein distribution and composition and their respective roles in CAA. Increased blood plasma concentrations of low density lipoproteins (LDL) and decreased concentrations of high density lipoproteins (HDL) both contribute to increased CHD in man and monkeys.
Pathways regulating plasma lipoprotein concentrations are under study. In addition, increased LDL cholesteryl oleate content has been associated with increased CAA. Isolated, perfused primate livers have been used to demonstrate that hepatic cholesteryl oleate secretion rate is correlated with LDL cholesteryl oleate enrichment and increased CAA. The enzyme in the liver responsible for cholesteryl oleate formation and secretion has been identified as acyl-CoA:cholesterol acyltransferase 2 (ACAT2). This enzyme has been cloned, expressed, and regulation by cholesterol and fatty acids is under investigation. Intrahepatic metabolism of cholesterol determines the type and extent of lipoprotein particle secretion by the liver, so we are quantifying entry and exit pathways for cholesterol in the liver. To accomplish this, we are examining transcriptional regulation of the genes controling hepatic cholesterol metabolism, particularly ACAT2 and cholesterol 7-a-hydroxylase, as this regulation is influenced by cholesterol and fatty acid type.
In sum, by delineating molecular aspects of diet responsiveness of cholesterol and lipoprotein metabolism in a nonhuman primate model of CAA, we are providing information that can eventually be helpful in development of strategies for prevention of coronary heart disease.
Figure 1: The role of ACAT1 and ACAT2 in cholesterol metabolism
Link to PubMed Database