The Nine Lives of ACAT Inhibitors

Abstract

Atherosclerosis is the product of excessive lipid accumulation and inflammation in the artery wall. The lipid that tops every list of suspects is cholesterol, which is the primary lipid in low-density lipoproteins (LDL). Cholesterol exists either as a simple molecule or as cholesterol esters, in which the hydroxyl group is linked to a fatty acyl moiety. In cells, cholesterol esters are synthesized in an intracellular reaction catalyzed by acyl coenzyme A (CoA):cholesterol acyltransferase (ACAT) enzymes.1,2 Owing to the discoveries of cholesterol esters in arterial lesions in 19103 and of ACAT activity in the mid 1900s,4 inhibiting ACAT has been considered as a strategy for preventing or treating atherosclerosis. Over the past 25 years, interest in ACAT inhibitors has waxed and waned as new studies advance knowledge in the field. Prominently reported and disappointing results from a recent human trial of an ACAT inhibitor5 dampened enthusiasm for this potential therapy. However, a study by Bell et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology 6 revives the idea of targeting ACAT enzymes and highlights a key unanswered question: Can ACAT2-specific inhibitors lower plasma cholesterol and treat or prevent atherosclerosis? See page 1814 After the discovery of the ACAT reaction, two rationales for inhibiting ACAT emerged. One, in retrospect, was perhaps overly simplistic: blocking cholesterol esterification in macrophages would diminish macrophage “foam cell” formation and thereby decrease atherosclerotic lesion development. The other was to decrease hepatic and intestinal cholesterol ester formation, resulting in decreases in plasma levels …