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 IN-(2, 6-diisopropylphenyl)tetradecylthioacetamide], suppressed the s ynthesis of cholesterol [C-14]oleate at 10(-9) similar to 10(-7) M in a concentration-dependent manner in both THP-I cell-derived macrophage s and foam cells prepared from aortic intima of rabbits fed a high cho lesterol diet. Incorporation of [H-3]cholesterol oleate-beta very low density lipoproteins was not inhibited by HL-004 at 10(-9) similar to 10(-7) M. Release of radioactivity from the cells loaded with [H-3]cho lesterol oleate-beta very low density lipoproteins was increased by th e inhibition of ACAT activity with HL-004. HL-004 did not affect on ac id and neutral cholesterol esterases. As a result, cholesterol ester c ontent in foam cells decreased. These data suggested that HL-004 decre ases cholesterol ester in foam cells by increasing the release of chol esterol and therefore might suppress atherosclerotic lesions.