Glibenclamide acts as an inhibitor of acyl-CoA : cholesterol acyltransferase enzyme

Sulfonylureas are used in the treatment of noninsulin-dependent diabetes me llitus. Little is known, however, about their effects on cholesterol metabo lism. We tested in the present study the effects of glibenclamide (GB) on c holesterol esterification (CE) in macrophage-derived cells, GB inhibited in tracellular accumulation of CE induced by acetylated LDL or oxidized LDL in J774 cells, but no such effect on total cholesterol, suggesting that the t arget of GB was acyl-CoA:cholestrol. acyltransferase (ACAT), In the cell-fr ee reconstitution ACAT assay, GB inhibited the ACAT activity with an IC50 v alue of 20 muM, Furthermore, GB effectively inhibited the ACAT activity of PMA-stimulated THP-1 cells to the undifferentiated level of THP-1. In the w hole-cell ACAT assay using CHO cells overexpressed with ACAT-1 or ACAT-2, G B inhibited the activity of both isozymes with similar potency. Our in vitr o data suggest that sulfonylurea could be a potential seed for a new genera tion of ACAT inhibitors. (C) 2000 Academic Press.