ACAT1

ACAT1, also termed sterol O-acyltransferase 1 (SOAT1), is an endoplasmic reticulum-associated enzyme that catalyzes the conversion of free cholesterol and long-chain fatty acyl-CoA into cholesteryl esters, thereby maintaining intracellular cholesterol homeostasis and promoting lipid droplet formation^[1][5]. Mechanistically, ACAT1-mediated cholesterol esterification limits excess free cholesterol accumulation and regulates cholesterol storage, linking membrane cholesterol balance to cellular metabolic adaptation^[1][6]. In macrophages, increased cholesterol influx activates ACAT1 and drives cholesteryl ester deposition, a process closely associated with foam-cell formation and early atherosclerotic lesion development^[7][2]. Experimental inhibition of ACAT activity enhances the pool of free cholesterol available for efflux and alters macrophage cholesterol metabolism, making ACAT1 a widely studied target in atherosclerosis models^[7][2]. Beyond cardiovascular disease, dysregulated ACAT1-dependent cholesterol esterification has been reported in cancer and neurodegenerative disorders, where elevated cholesteryl ester accumulation is linked to altered cellular cholesterol handling^[5][1][3]. Compared with the related isoform ACAT2/SOAT2, which is enriched in intestine and liver and participates in lipoprotein-associated cholesteryl ester production, ACAT1 is broadly expressed in peripheral tissues and is the dominant isoform involved in macrophage cholesterol storage and foam-cell biology^[6][4]. For experimental applications, inhibitors including avasimibe and the ACAT1-selective compound K-604 have been used to investigate cholesterol esterification, plaque remodeling, and disease-associated lipid metabolic pathways^[2][8].