Abstract

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 ∼ 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-β very low density lipoproteins was not inhibited by HL-004 at 10⁻⁹ ∼ 10⁻⁷ M. Release of radioactivity from the cells loaded with [³H]cholesterol oleate-β 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.