DEXAMETHASONE ENHANCES ACCUMULATION OF CHOLESTERYL ESTERS BY HUMAN MACROPHAGES

The effects of dexamethasone on Lipid accumulation by human monocyte-derived macrophages were investigated. Preincubation of macrophages with dexamethasone for a period of 16-20 h resulted in a reproducible increase (3.5-fold) in the incorporation of oleate into cholesteryl esters. The effect was specific because no alterations were observed in oleate incorporation into triglycerides or phospholipids. Measurement of cellular cholesteryl esters indicated a fourfold increase after preincubation with dexamethasone. This increase was mediated by opposite effects on synthesis and breakdown of these lipids. Dexamethasone produced a 60% increase in activity of the enzyme acyl-CoA: cholesterol O-acyltransferase (ACAT), active in synthesis of cholesteryl esters, and a 40% decrease in that of neutral cholesteryl esterase, active in cholesteryl ester breakdown. The increased ACAT activity appeared to reflect increased mRNA for the enzyme. The effects of dexamethasone on cholesteryl ester accumulation by macrophages reached statistical significance at a concentration of 100 nM. They were dose dependent, and saturation was observed at around 1 mu M. The effects were significant at low concentrations of cholesterol in the medium. At high-medium cholesterol, there was a large cholesterol-induced increase in ACAT activity that obscured most of the effect of dexamethasone. In general, the data suggest that high glucocorticoid levels enhance Lipid accumulation by macrophages and thus would have an atherogenic action that is independent of serum cholesterol.