Vol. 287, Issue 1, 115-121, October 1998

Stimulation of Cholesterol Release from Rabbit Foam Cells by the Action of a New Inhibitor for Acyl CoA:Cholesterol Acyltransferase (ACAT), HL-004

Itsuko Ishii, Noriko Yokoyama, Mamoru Yanagimachi, Naoya Ashikawa, Masayuki Hata, Shigeru Murakami¹, Yumiko Asami¹, Nobuhiro Morisaki², Yasushi Saito², Shigeru Ohmori³ and Mitsukazu Kitada³

Faculty of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

A new inhibitor of acyl CoA:cholesterol acyltransferase (ACAT), HL-004 [N-(2, 6-diisopropylphenyl)tetradecylthioacetamide], suppressed the synthesis of cholesterol [¹⁴C]oleate at 10⁹ ~ 10⁷ 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- very low density lipoproteins was not inhibited by HL-004 at 10⁹ ~ 10⁷ M. Release of radioactivity from the cells loaded with [³H]cholesterol oleate- 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.