Lawrence L. Rudel, PhD
Cholesterol and Lipoprotein Metabolism Studies using Primate and Mouse Models
Complications arising from coronary heart disease (CHD) 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 have followed these studies by developing genetically engineered mouse models that allow us to evaluate selected gene targets. 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 in our animal models. Other factors in cholesterol metabolism also contribute.
Pathways regulating plasma lipoprotein concentrations as affected by dietary cholesterol and fatty acid type are under study. Further, the monkey experiments have shown that lipoprotein particle composition, i.e. increased LDL cholesteryl oleate content, is consistently 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 to be acyl-CoA:cholesterol acyltransferase 2 (ACAT2), also termed steryl 0-acyl transferase 2 (SOAT2). This enzyme has been cloned, expressed, and its regulation by cholesterol and fatty acids is under investigation. Mouse models of SOAT2 deletion and tissue specific expression have been valuable in defining the essential role of this enzyme in lipoprotein metabolic pathways associated with atherogenesis. Promotion of LDL particle retention in the intima of arteries has been a demonstrated consequence of cholesterol oleate enrichment. 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 controlling hepatic cholesterol metabolism, particularly SOAT2, 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, and subsequently evaluating the role of specific enzymes and pathways in genetically engineered mouse models, we are providing information that hopefully will be helpful in development of strategies for prevention and treatment of coronary heart disease. We have begun translational studies by evaluating selective small molecule SOAT2 inhibitors with the hope that compounds will be identified that can eventually prove useful in treatment of CHD patients.
Figure 1: The role of ACAT1 and ACAT2 in cholesterol metabolism
Link to PubMed Database