VASTATINS INHIBIT CHOLESTEROL ESTER ACCUMULATION IN HUMAN MONOCYTE-DERIVED MACROPHAGES

Human monocyte-derived macrophages were incubated for 48 hours in Medium 199 with 1% human serum albumin, and with 100-mu-g acetyl low density lipoprotein (LDL) or beta-very low density lipoprotein (beta-VLDL), with or without various concentrations of compactin, lovastatin, simvastatin, or pravastatin. The mass of free (FC) and esterified (CE) cholesterol was determined, as well as the incorporation of [1-C-14]acetate in sterols, that of [1-C-14]oleate in CE, and that of [methy-C-14]choline in phospholipids. Moreover, we assessed the high-affinity association and degradation of I-125-labeled acetyl LDL. Compactin markedly decreased the cellular accumulation of CE induced by acetyl LDL or beta-VLDL and increased the content of FC. Compactin also decreased the incorporation of [1-C-14]oleate in CE (by 70-90%) in incubations with or without added lipoproteins. The half-maximal inhibitory concentration for this effect of compactin was 30 nM. Lovastatin and simvastatin were more potent, but pravastatin was about 100-fold less potent. Although compactin also caused a clear inhibition of cholesterol synthesis in the presence of acetyl LDL, the effect on CE formation did not seem to be related to decreased cholesterol synthesis, since this was already very low in the presence of acetyl LDL. Compactin did not affect the association and degradation of labeled acetyl LDL and also had no effect on the rate of cholesterol loss after preloading the cells with CE by incubation with acetyl LDL. However, compactin had a slight stimulatory effect on the synthesis of phosphatidylcholine and sphingomyelin when compactin was added to incubations in the presence of acetyl LDL. We conclude that vastatins can decrease the supply of FC toward the enzyme, acyl-coenzyme A: cholesterol acyltransferase, by trapping it in phospholipid-containing pools.