Mevinolin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, suppresses enterocyte esterification of exogenous but not endogenous cholesterol.
Mevinolin (lovastatin), a competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase, directly inhibited acyl-CoA cholesteryl acyltransferase in rabbit intestinal microsomes at a dose of 20 micrograms/ml or more. Lineweaver-Burk analysis showed a competitive type of inhibition with respect to oleoyl-CoA. In cultured intestinal Caco-2 cells, mevinolin reduced [14C]oleate incorporation into cholesteryl-esters by 86% of controls at doses as low as 0.1 micrograms/ml. However, in cells whose activity of acyl-CoA cholesteryl acyltransferase was stimulated 7-fold by 10 mM mevalonolactone, a significant inhibitory effect on cholesteryl-ester formation could not be detected, even at 40 micrograms/ml of mevinolin. In contrast, cells supplied with liposomal cholesterol or cholesterol derived from low-density lipoproteins showed a marked reduction of cholesteryl-ester formation in the presence of 10 or 0.1 micrograms/ml of mevinolin, respectively. It is concluded that the observed suppressive effects of mevinolin on cholesterol esterification in cultured Caco-2 cells are indirect and possibly caused by changes in the acyl-CoA cholesteryl acyltransferase substrate pool or intracellular cholesterol transport.
Fellermann
K
K
Department of Internal Medicine II, University of Ulm, Germany.
Reimann
F M
FM
Herold
G
G
Stange
E F
EF
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004951:Esterification; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008081:Liposomes / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008861:Microsomes / Q000378:metabolism; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D013379:Substrate Specificity
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008081:Liposomes; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002785:Sterol O-Acyltransferase