Sterol O-acyltransferase (ACAT) (ACAT)

Sterol O-acyltransferase (ACAT) is an essential intracellular enzyme located in the endoplasmic reticulum that catalyzes the conversion of free cholesterol into cholesteryl esters using long-chain fatty acyl-CoA. This process is critical for maintaining cellular cholesterol homeostasis, as it prevents the toxic accumulation of unesterified cholesterol in cell membranes by sequestering it into cytoplasmic lipid droplets. In humans, the enzyme exists in two distinct isoforms: ACAT1, which is ubiquitously expressed and particularly prominent in macrophages and the brain, and ACAT2, which is primarily localized to the liver and small intestine where it facilitates the assembly of lipoproteins like chylomicrons and VLDL. The role of ACAT in the formation of foam cells within atherosclerotic plaques initially made it a major therapeutic target for cardiovascular disease. However, despite success in animal models, large-scale clinical trials for non-selective ACAT inhibitors like avasimibe and pactimibe failed to demonstrate efficacy in reducing plaque volume and, in some cases, showed potentially harmful effects or adrenal toxicity. Beyond cardiovascular health, ACAT inhibition is currently being investigated for neurodegenerative conditions like Alzheimer's disease, where it may modulate amyloid-beta production, and for various cancers, where it appears to regulate tumor cell proliferation and anti-tumor immunity. Recent research continues to explore isoform-specific inhibitors to overcome previous safety challenges and unlock the therapeutic potential of this metabolic pathway.

Other names

Acyl-CoA:cholesterol acyltransferaseAcyl-coenzyme A:cholesterol acyltransferaseSOATCholesterol acyltransferaseSterol O-acyltransferase 1Sterol O-acyltransferase 2ACAT1ACAT2

Inhibition of sterol O-acyltransferase, preventing the esterification of free cholesterol into cholesteryl esters