Inhibition of cellular cholesterol esterification can decrease low density lipoprotein receptor number in human fibroblasts.
In fibroblasts deprived of exogenous cholesterol to induce low density lipoprotein receptors there is a continuing flux of cholesterol esterification. The structurally unrelated inhibitors of acyl-CoA; cholesterol acyl-transferase, progesterone, trimethylcyclohexanyl mandelate and 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl] propanamide, (58035), could all inhibit this basal rate of esterification within 1h of addition. Exposure of cholesterol-deprived fibroblasts for 17h to progesterone or trimethylcyclohexanyl mandelate caused decreased specific binding and metabolism of low density lipoprotein. The effect was not a direct inhibition of lipoprotein binding; it was time dependent and followed from the reversible inhibition of cholesterol esterification by these two compounds. The irreversible inhibition of esterification by 58035 left the receptor number unaffected. The results indicate that down regulation of low density lipoprotein receptors is initiated by accumulation of cholesterol in a specific intracellular pool. Inhibition of cholesterol esterification by progesterone and trimethylcyclohexanyl mandelate causes accumulation of cholesterol in this pool but 58035 does not.
D000577:Amides / Q000494:pharmacology; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D003495:Cyclandelate / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017646:Organosilicon Compounds; D011374:Progesterone / Q000494:pharmacology; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000577:Amides; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D017646:Organosilicon Compounds; D011973:Receptors, LDL; D003495:Cyclandelate; D011374:Progesterone; C040256:SAN 58035; D002785:Sterol O-Acyltransferase