Previous studies with a number of selective acylcoenzyme A:
cholesterol acyltransferase (ACAT) inhibitors in several animal models have demonstrated significant reductions in plasma
cholesterol and, in some studies,
triglyceride levels. This study was conducted to examine the effects of two ACAT inhibitors,
CL 283,546 and
CL 283,796, in
cholesterol-high fat diet fed African green monkeys, a relevant primate model of
hyperlipidemia and coronary artery
atherosclerosis. Treatment with
CL 283,546 or
CL 283,796 resulted in significant reductions (ca. 25-30%) in total plasma
cholesterol at both 10 and 30 mg/kg per day doses. This reduction in plasma
cholesterol was due almost entirely to reduction in
low density lipoprotein (
LDL) cholesterol (ca. 45%) without significantly affecting
high density lipoprotein (
HDL) cholesterol,
very low density lipoprotein +
intermediate density lipoprotein (VLDL +
IDL) cholesterol, or
triglyceride concentrations. There were no significant effects on plasma concentrations of
apolipoproteins A-I, E, or B and, thus, the reduction seen in
LDL cholesterol appears to be due to a diminished
cholesterol content of
LDL particles. Our studies revealed that treatment with these compounds did not reduce
cholesterol absorption, which was somewhat surprising as ACAT inhibitors are generally thought to exert their hypolipidemic effects, at least in part, by inhibition of intestinal
cholesterol absorption. Our data are consistent with a principal activity of these drugs on the liver to reduce
cholesteryl ester secretion in VLDL, leading to a diminished
LDL-cholesterol content, and, presumably, enhanced biliary
cholesterol-
bile acid excretion.