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

摘要: Abstract Background Acyl-coenzyme A:cholesterol O -acyltransferase-1 (ACAT-1), a major ACAT isozyme in macrophages, plays an essential role foam cell formation atherosclerotic lesions. However, whether pharmacological inhibition of macrophage ACAT-1 causes exacerbation or suppression atherosclerosis is controversial. Methods and results We developed characterized novel inhibitor, K-604. The IC 50 values K-604 for human ACAT-2 were 0.45 102.85μmol/L, respectively, indicating that 229-fold more selective ACAT-1. Kinetic analysis indicated the was competitive with respect to oleoyl-coenzyme A K i value 0.378μmol/L. Exposure monocyte-derived macrophages inhibited cholesterol esterification 68.0nmol/L. Furthermore, efflux from THP-1 HDL 3 apolipoprotein A-I enhanced by Interestingly, administration F1B hamsters on high-fat diet at dose ≥1mg/kg suppressed fatty streak lesions without affecting plasma levels. Conclusions K-604, potent inhibitor ACAT-1, development animal model levels, providing direct evidence arterial walls leads atherosclerosis.