THE STRUCTURE OF ACYL-COENZYME A-CHOLESTEROL ACYLTRANSFERASE AND ITS POTENTIAL RELEVANCE TO ATHEROSCLEROSIS

Acyl coenzyme A-cholesterol acyltransferase (ACAT) catalyzes the forma tion of intracellular cholesterol esters. It is present in a variety o f tissues and is believed to play significant roles in cholesterol hom eostasis. Under pathologic conditions, accumulation of the ACAT reacti on product as cytoplasmic cholesterol ester lipid droplets within macr ophages and smooth muscle cells is a characteristic feature of early l esions of human atherosclerotic plaques. ACAT is a membrane protein lo cated in the endoplasmic reticulum. Its activity is susceptible to ina ctivation by detergents, and it has never been purified to homogeneity ; no antibodies directed against it have been reported. Through a soma tic cell and molecular genetic approach, we have recently succeeded in molecular cloning and functional expression of a human macrophage ACA T cDNA. This cDNA contains an open reading frame of 1650 base pairs en coding an integral membrane protein of 550 amino acids. Protein homolo gy analysis shows that the predicted protein sequence shaves shout reg ions 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 biochemis try and molecular biology. If will speed up the design of specific ACA T inhibitors as drugs that may provide move effective therapeutic trea tment or prevention of atherosclerosis. In addition, studies on the ph ysiologic roles of ACAT in various tissues can now be undertaken throu gh transgenic animal research.