Ishii I, Yokoyama N, Yanagimachi M, Ashikawa N, Hata M, Murakami S, Asami Y, Morisaki N, Saito Y, Ohmori S, Kitada M
Faculty of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
J Pharmacol Exp Ther. 1998 Oct;287(1):115-21.
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.
一种新的酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂HL - 004 [N -（2,6 - 二异丙基苯基）十四烷基硫代乙酰胺]，在10^(-9)至10^(-7) M浓度范围内，以浓度依赖的方式抑制了THP - 1细胞衍生的巨噬细胞和由喂食高胆固醇饮食的兔主动脉内膜制备的泡沫细胞中胆固醇[14C]油酸酯的合成。在10^(-9)至10^(-7) M浓度下，HL - 004对[3H]胆固醇油酸酯-β极低密度脂蛋白的掺入没有抑制作用。HL - 004抑制ACAT活性后，增加了加载[3H]胆固醇油酸酯-β极低密度脂蛋白的细胞中放射性的释放。HL - 004对酸性和中性胆固醇酯酶没有影响。结果，泡沫细胞中的胆固醇酯含量降低。这些数据表明，HL - 004通过增加胆固醇的释放来降低泡沫细胞中的胆固醇酯，因此可能抑制动脉粥样硬化病变。
