The influence of the
acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitor,
CL 277082, on macrophage
cholesteryl ester accumulation in a rabbit
carrageenan granuloma macrophage-foam cell model was studied. Diets were supplemented with 0.3%
cholesterol and 6%
peanut oil with or without the inhibitor (0.25%) for 4 weeks prior to
granuloma induction, and macrophage-rich
granuloma tissue was harvested 14 days after
carrageenan injection. Serum
cholesterol was monitored biweekly, and plasma
lipoproteins were isolated terminally. Total, free and esterified
cholesterol contents were measured in hepatic and
granuloma tissue. In hepatic tissue, administration of
CL 277082 resulted in an 80% reduction in the content of total
cholesterol, a 37% decrease in free
cholesterol, and a 90% decrease in esterified
cholesterol. Similarly, in macrophage-rich
granuloma tissue, total
cholesterol content was decreased by 44%, and esterified
cholesterol content by 61%, with no change in free
cholesterol. Additionally,
CL 277082 was shown to inhibit
granuloma tissue ACAT activity by 45%, VLDL mass was decreased slightly,
LDL mass increased 3.4-fold and HDL mass was similar in both the inhibitor-treated and control animals.
CL 277082 resulted in a 57% decrease in VLDL
cholesteryl ester content and a 4.5-fold increase in
triacylglycerol.
Cholesteryl ester content in
LDL was decreased by 31% and
LDL triacylglycerol was increased 5.2-fold, while the only change in HDL composition was a 3.5-fold increase in
triacylglycerol. The reductions in both hepatic tissue and macrophage-rich
granuloma tissue esterified
cholesterol accumulation are considered to be due largely to cellular ACAT inhibition, and the altered distribution and composition of the plasma
lipoproteins.