Update on the role of acyl-CoA:cholesterol acyltransferase inhibitors in atherosclerosis

Cardiovascular disease is one of the leading causes of mortality and morbidity in industrialised nations. Hypercholesterolaemia is one of a number of risk factors identified that influences the development and progression of atherosclerosis. While drugs such as HMGCoA reductase inhibitors or statins have been shown to significantly reduce cholesterol levels and the risk for cardiovascular disease, there is still a pressing need to identify other compounds that might further reduce the risk. One such class of drugs, currently in preclinical and clinical studies, is acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors. Two isoforms of ACAT have been identified; ACAT₁ has a more ubiquitous distribution in steroidogenic tissue, pancreas, intestine and macrophages and ACAT₂ is predominantly expressed in hepatocytes and intestines. In human tissues, ACAT₂ expression is high in foetal hepatocytes but declines in adult hepatocytes. Its expression remains unchanged in foetal and adult human intestines. ACAT enzymes participate in the assembly of chylomicrons and very low density lipoproteins (triglyceride rich lipoproteins) and also in the formation of cholesteryl ester storage droplets within cells residing in the vessel wall. The initial results from preclinical and clinical studies suggest that ACAT inhibitors may have a beneficial effect in altering lipid profiles and in retarding the progression of atherosclerotic disease.