ACAT Inhibition

Abstract

Ahallmark of the atherosclerotic plaque is the accumulation of lipid-laden foam cells that are derived from macrophages or smooth muscle cells (SMCs).1,2 Cholesterol from modified lipoproteins is taken up and either stored in intracellular lipid droplets or delivered to extracellular cholesterol acceptors. Cellular free cholesterol can be exported to nascent HDL and activate the reverse cholesterol transport system, but when it accumulates in large amounts it can induce toxic changes leading to cell death. Conversely, esterified cholesterol is a more inert form of cholesterol for storage, but is not available for efflux to extracellular cholesterol acceptors. Acyl-coenzyme A (CoA): cholesterol acyltransferase (ACAT) esterifies excess free cholesterol and regulates cellular cholesterol homeostasis. ACAT occurs in two isoforms, ACAT-1 and ACAT-2. Whereas liver and intestine express both ACAT-1 and ACAT-2, macrophages and SMCs express ACAT-1 only.3 Nonselective inhibition of ACAT has the potential to both lower plasma lipids and to reduce foam cell formation.3,4 However, the therapeutic potential of ACAT inhibitors is not without controversy, because data have been published suggesting beneficial effects on experimental atherosclerosis as well as negative effects on macrophage viability.5–7 Furthermore, elimination of macrophage ACAT-1 is associated with increased atherosclerotic lesion formation in murine models.8 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Rong et al point to SMCs as a possible explanation for the apparently contradictory effects of ACAT inhibition.9 See page 122 In this study, Rong et …