ACAT

Acyl-CoA:cholesterol acyltransferase (ACAT/SOAT) converts cholesterol to cholesteryl esters and regulates cellular cholesterol homeostasis^[1]. Mechanistically, ACAT uses cholesterol and long-chain fatty-acyl-CoA to form cholesteryl esters, thereby supporting intracellular cholesterol storage, hepatic and intestinal lipoprotein assembly, and neutral lipid metabolism^[2][3]. In atherosclerosis biology, ACAT-derived cholesteryl ester accumulation in macrophages contributes to foam cell formation, while ACAT inhibition retards foam cell formation in aortic smooth muscle cells without significant cytotoxicity in that model^[2][4]. Disease models further separate isoform functions: ACAT2 deficiency limits cholesterol absorption in cholesterol-fed mice, reduces atherosclerosis in LDL receptor-deficient mice, and reduces esterified cholesterol sequestration in lysosomal acid lipase-deficient mice^[5][6][7]. Compared with ACAT1, which shows broad tissue expression and supports cholesterol esterification in many cells, ACAT2 is emphasized in enterocytes, hepatocytes, liver, and small intestine, making ACAT2 a distinct target for intestinal absorption, hepatic cholesterol handling, and apoB-lipoprotein cholesteryl ester production^[3][5][8]. For experimental applications, pyripyropene A shows strong ACAT2 selectivity, beauveriolide derivative BVD327 reduces atherosclerotic lesions in Apoe knockout mice, and newer selective ACAT2 antagonists provide scaffolds for ACAT2-centered inhibitor design^[9][10][11].