The structure of acyl coenzyme A-cholesterol acyltransferase and its potential relevance to atherosclerosis

Acyl coenzyme A-cholesterol acyltransferase (ACAT) catalyzes the formation of intracellular cholesterol esters. It is present in a variety of tissues and is believed to play significant roles in cholesterol homeostasis. Under pathologic conditions, accumulation of the ACAT reaction product as cytoplasmic cholesterol ester lipid droplets within macrophages and smooth muscle cells is a characteristic feature of early lesions of human atherosclerotic plaques. ACAT is a membrane protein located in the endoplasmic reticulum. Its activity is susceptible to inactivation by detergents, and it has never been purified to homogeneity; no antibodies directed against it have been reported. Through a somatic cell and molecular genetic approach, we have recently succeeded in molecular cloning and functional expression of a human macrophage ACAT cDNA. This cDNA contains an open reading frame of 1650 base pairs encoding an integral membrane protein of 550 amino acids. Protein homology analysis shows that the predicted protein sequence shares short regions of homology with other enzymes involved in the catalysis of acyl adenylate formation with subsequent acyl thioester formation and acyl transfer. The ACAT cDNA will enable the investigation of ACAT biochemistry and molecular biology. It will speed up the design of specific ACAT inhibitors as drugs that may provide more effective therapeutic treatment or prevention of atherosclerosis. In addition, studies on the physiologic roles of ACAT in various tissues can now be undertaken through transgenic animal research.