A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels

Background Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1), a major ACAT isozyme in macrophages, plays an essential role in foam cell formation in atherosclerotic lesions. However, whether pharmacological inhibition of macrophage ACAT-1 causes exacerbation or suppression of atherosclerosis is controversial. Methods and results We developed and characterized a novel ACAT inhibitor, K-604. The IC50 values of K-604 for human ACAT-1 and ACAT-2 were 0.45 and 102.85 μmol/L, respectively, indicating that K-604 is 229-fold more selective for ACAT-1. Kinetic analysis indicated that the inhibition was competitive with respect to oleoyl-coenzyme A with a Ki value of 0.378 μmol/L. Exposure of human monocyte-derived macrophages to K-604 inhibited cholesterol esterification with IC50 of 68.0 nmol/L. Furthermore, cholesterol efflux from THP-1 macrophages to HDL3 or apolipoprotein A-I was enhanced by K-604. Interestingly, administration of K-604 to F1B hamsters on a high-fat diet at a dose of ≥1 mg/kg suppressed fatty streak lesions without affecting plasma cholesterol levels. Conclusions K-604, a potent and selective inhibitor of ACAT-1, suppressed the development of atherosclerosis in an animal model without affecting plasma cholesterol levels, providing direct evidence that pharmacological inhibition of ACAT-1 in the arterial walls leads to suppression of atherosclerosis.