Effects of NTE-122, a novel acyl-CoA : cholesterol acyltransferase inhibitor, on cholesterol esterification and high-density lipoprotein-induced cholesterol efflux in macrophages

We investigated the effects of a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, NTE-122 (trans-1,4-bis[[l -cyclohexyl-3 -(4-dimethylamin o phenyl)ureido]methyl] cyclohexane), on ACAT activities in macrophages ori ginating from several species and high-density lipoprotein (HDL)-induced ch olesterol efflux in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cel ls. NTE-122 inhibited cell-free ACAT activities in human PMA-treated THP-1 cells and mouse J774.1 cells with IC50 values of 0.88 and 360 nM, respectiv ely. NTE-122 competively inhibited the ACAT activity in PMA-treated THP-1 c ells. NTE-122 also inhibited cellular ACAT activities in PMA-treated THP-1 cells, rat peritoneal macrophages and J774.1 cells with IC50 values of 3.5, 84 and 6800 nM, respectively. Furthermore, NTE-122 prevented cholesterol a ccumulation in PMA-treated THP-1 cells incubated with acetylated low densit y lipoprotein, simultaneously with HDL, while it caused accumulation of a s ignificant amount of free cholesterol in the absence and even in the presen ce of HDL. NTE-122 also enhanced HDL-induced cholesterol efflux from establ ished foam cells converted from PMA-treated THP-1 cells. These results sugg est that NTE-122, capable of inhibiting macrophage ACAT activity in humans more strongly than those in the other species, exhibits anti-atherogenic ef fects by preventing the foam cell formation and enhancing the foam cell reg ression in humans.