DEXAMETHASONE IMPAIRS CHOLESTEROL EGRESS FROM A LOCALIZED LIPOPROTEINDEPOT IN-VIVO

Plasma high density lipoproteins play a central role in the prevention and regression of atherosclerosis, as they are known to promote egres s of cholesterol from cells. Glucocorticoids increase plasma HDL, but enhance esterification of cholesterol in macrophages in vitro. A novel model to measure cholesterol egress from a well defined depot in vivo was used currently to study the effect of dexamethasone on reverse ch olesterol transport. Cationized LDL (cat LDL) (200 mu g cholesterol) w as injected into the rectus femoris muscle of mice and the egress of c holesterol was studied as a function of time. Daily subcutaneous injec tion of dexamethasone (1.25 mu g) raised plasma HDL levels by 40-80%. In mice injected with cat LDL labeled with H-3-cholesterol, daily trea tment with dexamethasone slowed the loss of labeled cholesterol from t he depot. With dexamethasone, there was no removal of the mass of lipo protein cholesterol up to 14 days after injection of cat LDL, while in the controls 75% of the exogenous cholesterol mass had been cleared f rom the depot. When the cat LDL had been labeled with H-3-cholesteryl eater (H-3-CE), apparent hydrolysis of H-3-CE amounted to 46, 75 and 9 7% in controls, but only to 20, 48 and 65% in dexamethasone treated mi ce on days 4, 8 and 14, respectively. In addition, dexamethasone stimu lated cholesterol re-esterification as evidenced by recovery of 80% of the retained cholesterol mass as CE. In experiments with cultured mac rophages exposed to modified LDL, dexamethasone increased the amount o f labeled cholesteryl ester by 50-75% as compared to controls. Histolo gical examination of the rectus femoris muscle after injection of cat LDL showed that in dexamethasone treated mice cellular infiltration wa s sparser on day 4, but not on day 8, and persisted longer than in con trols. In conclusion, dexamethasone treatment impeded cholesterol egre ss from a lipoprotein depot by: a) reduction of early inflow of mononu clear cells; b) partial inhibition of cholesteryl ester hydrolysis, an d c) enhancement of cholesterol esterification. The latter effect did not permit cholesterol egress from the injected site even in the prese nce of high plasma HDL in dexamethasone treated mice. (C) 1998 Elsevie r Science Ireland Ltd. All rights reserved.