Dexamethasone impairs cholesterol egress from a localized lipoprotein depot in vivo.
Plasma high density lipoproteins play a central role in the prevention and regression of atherosclerosis, as they are known to promote egress 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 cholesterol transport. Cationized LDL (cat LDL) (200 microg cholesterol) was injected into the rectus femoris muscle of mice and the egress of cholesterol was studied as a function of time. Daily subcutaneous injection of dexamethasone (1.25 microg) raised plasma HDL levels by 40-80%. In mice injected with cat LDL labeled with 3H-cholesterol, daily treatment with dexamethasone slowed the loss of labeled cholesterol from the depot. With dexamethasone, there was no removal of the mass of lipoprotein cholesterol up to 14 days after injection of cat LDL, while in the controls 75% of the exogenous cholesterol mass had been cleared from the depot. When the cat LDL had been labeled with 3H-cholesteryl ester (3H-CE), apparent hydrolysis of 3H-CE amounted to 46, 75 and 97% in controls, but only to 20, 48 and 65% in dexamethasone treated mice on days 4, 8 and 14, respectively. In addition, dexamethasone stimulated cholesterol re-esterification as evidenced by recovery of 80% of the retained cholesterol mass as CE. In experiments with cultured macrophages exposed to modified LDL, dexamethasone increased the amount of labeled cholesteryl ester by 50-75% as compared to controls. Histological examination of the rectus femoris muscle after injection of cat LDL showed that in dexamethasone treated mice cellular infiltration was sparser on day 4, but not on day 8, and persisted longer than in controls. In conclusion, dexamethasone treatment impeded cholesterol egress from a lipoprotein depot by: a) reduction of early inflow of mononuclear cells; b) partial inhibition of cholesteryl ester hydrolysis, and c) enhancement of cholesterol esterification. The latter effect did not permit cholesterol egress from the injected site even in the presence of high plasma HDL in dexamethasone treated mice.
Stein
O
O
Department of Experimental Medicine and Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Dabach
Y
Y
Hollander
G
G
Ben-Naim
M
M
Halperin
G
G
Stein
Y
Y
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000008:administration & dosage / Q000097:blood*; D003907:Dexamethasone / Q000494:pharmacology*; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000494:pharmacology*; D006868:Hydrolysis / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005938:Glucocorticoids; D003907:Dexamethasone; D002785:Sterol O-Acyltransferase