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[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), on ACAT activities in macrophages originating from several species and high-density lipoprotein (HDL)-induced cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. 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, respectively. NTE-122 competively inhibited the ACAT activity in PMA-treated THP-1 cells. 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 accumulation in PMA-treated THP-1 cells incubated with acetylated low density lipoprotein, simultaneously with HDL, while it caused accumulation of a significant amount of free cholesterol in the absence and even in the presence of HDL. NTE-122 also enhanced HDL-induced cholesterol efflux from established foam cells converted from PMA-treated THP-1 cells. These results suggest that NTE-122, capable of inhibiting macrophage ACAT activity in humans more strongly than those in the other species, exhibits anti-atherogenic effects by preventing the foam cell formation and enhancing the foam cell regression in humans.
Azuma
Y
Y
Central Research Institute, Nissin Food Products Co., Ltd., Kusatsu, Shiga, Japan.
Kawasaki
T
T
Ikemoto
K
K
Ohno
K
K
Yamada
T
T
Yamasaki
M
M
Nobuhara
Y
Y
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; C111531:NTE 122; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D013755:Tetradecanoylphorbol Acetate