Use of transgenic animal models to study enzymes involved in lipoprotein metabolism and atherosclerosis

Lecithin cholesteryl acyltransferase (LCAT) plays a major role in HDL metabolism by facilitating the esterification of free cholesterol present in circulating plasma lipoproteins. We have investigated the role that this enzyme plays in reverse cholesterol transport and the development of atherosclerosis by inducing the formation of aortic lesions using an atherogenic diet in transgenic mice and rabbits that overexpress human LCAT. Despite elevated plasma concentrations of HDL-cholesterol and apolipoprotein (apo) A-I, LCAT transgenic mice have enhanced diet-induced aortic atherosclerosis. In contrast, LCAT transgenic rabbits have increased plasma concentrations of HDL-cholesterol and apoA-I, reduced levels of apoB-containing lipoproteins and decreased aortic atherosclerosis. Reduced plasma concentrations of the proatherogenic apo-B-containing lipoproteins in rabbits but not in mice, as well as the presence of a "dysfunctional" HDL in LCAT transgenic mice may account for the differences in atherosclerosis between the two LCAT transgenic animal models. Our findings demonstrate the importance of LCAT in modulating the process of reverse cholesterol transport and atherosclerosis.