Stimulation of cholesterol release from rabbit foam cells by the action of a new inhibitor for acyl CoA:cholesterol acyltransferase (ACAT), HL-004.
A new inhibitor of acyl CoA:cholesterol acyltransferase (ACAT), HL-004 [N-(2, 6-diisopropylphenyl)tetradecylthioacetamide], suppressed the synthesis of cholesterol [14C]oleate at 10(-9) approximately 10(-7) M in a concentration-dependent manner in both THP-1 cell-derived macrophages and foam cells prepared from aortic intima of rabbits fed a high cholesterol diet. Incorporation of [3H]cholesterol oleate-beta very low density lipoproteins was not inhibited by HL-004 at 10(-9) approximately 10(-7) M. Release of radioactivity from the cells loaded with [3H]cholesterol oleate-beta very low density lipoproteins was increased by the inhibition of ACAT activity with HL-004. HL-004 did not affect on acid and neutral cholesterol esterases. As a result, cholesterol ester content in foam cells decreased. These data suggested that HL-004 decreases cholesterol ester in foam cells by increasing the release of cholesterol and therefore might suppress atherosclerotic lesions.
Faculty of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
I
I
Ishii
N
N
Yokoyama
M
M
Yanagimachi
N
N
Ashikawa
M
M
Hata
S
S
Murakami
Y
Y
Asami
N
N
Morisaki
Y
Y
Saito
S
S
Ohmori
M
M
Kitada
D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000083:Acetanilides; D004791:Enzyme Inhibitors; C092284:HL 004; D008075:Lipoproteins, HDL; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D013755:Tetradecanoylphorbol Acetate