Yukimasa Azuma, Takashi Kawasaki, Kiyohito Ikemoto, Katsutoshi Ohno,
Toshihiro Yamada, Masahiro Yamasaki and Yoichi Nobuhara
Central Research Institute, Nissin Food Products Co., Ltd., 2247, Noji,
Kusatsu, Shiga 525-0055, Japan
Abstract: 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.
Keywords: NTE-122, Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor,
Macrophage, Cholesterol accumulation, Cholesterol efflux