Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages.
HMG-CoA reductase inhibitors simvastatin, fluvastatin and fluvastatin enantiomers (0.1 to 5 microM) were utilized to block both mevalonate formation and cholesterol esterification in mouse peritoneal macrophages in the presence of a large excess of cholesterol supplied by acetylated LDL. Supplementation of cultures with mevalonate fully reversed, in a dose-dependent manner, the inhibitory effect of the drugs on cholesterol esterification. Mevalonate alone, in the range of the tested concentrations, did not affect cholesterol esterification in the absence of the HMG-CoA reductase inhibitors, indicating that its effect was linked to the restoration of the endogenous pool depleted by the pharmacological block of HMG-CoA reductase. The inhibitory effect of fluvastatin was also prevented by the non-sterol mevalonate isoprenoid derivative geranylgeraniol. Evaluation of fluvastatin enantiomers demonstrated the stereospecificity of drug action with most of the effect associated to the antipode with the highest inhibitory activity of HMG-CoA reductase. We conclude that mevalonate or a mevalonate product(s), possibly a non-sterol derivative(s), are required in cholesterol esterification induced by acetylated LDL in macrophages.
Bernini
F
F
Institute of Pharmacology and Pharmacognosy, University of Parma, Italy.
Didoni
G
G
Bonfadini
G
G
Bellosta
S
S
Fumagalli
R
R
D000107:Acetylation; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004951:Esterification / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019821:Simvastatin
D000924:Anticholesteremic Agents; D002788:Cholesterol Esters; D004224:Diterpenes; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008077:Lipoproteins, LDL; D000077340:Fluvastatin; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; C017338:geranylgeraniol; D008798:Mevalonic Acid