Acyl coenzyme A : cholesterol acyltransferase types 1 and 2: structure andfunction in atherosclerosis

Two enzymes are responsible for cholesterol ester formation in tissues, acy l coenzyme A:cholesterol acyltransferase types 1 and 2 (ACAT1 and ACAT2). T he available evidence suggests different cell locations, membrane orientati ons, and metabolic functions for each enzyme. ACAT1 and ACAT2 gene disrupti on experiments in mice have shown complementary results, with ACAT1 being r esponsible for cholesterol homeostasis in the brain, skin, adrenal, and mac rophages. ACAT1 -/- mice have less atherosclerosis than their ACAT1 +/+ cou nterparts, presumably because of the decreased ACAT activity in the macroph ages. By contrast, ACAT2 -/- mice have limited cholesterol absorption in th e intestine, and decreased cholesterol ester content in the liver and plasm a lipoproteins. Almost no cholesterol esterification was found when liver a nd intestinal microsomes from ACAT2 -/- mice were assayed. Studies in non-h uman primates have shown the presence of ACAT1 primarily in the Kupffer cel ls of the liver, in non-mucosal cell types in the intestine, and in kidney and adrenal cortical cells, whereas ACAT2 is present only in hepatocytes an d in intestinal mucosal cells. The membrane topology for ACAT1 and ACAT2 is also apparently different, with ACAT1 having a serine essential for activi ty on the cytoplasmic side of the endoplasmic reticulum membrane, whereas t he analogous serine is present on the lumenal side of the endoplasmic retic ulum for ACAT2. Taken together, the data suggest that cholesterol ester for mation by ACAT1 supports separate functions compared with cholesterol ester ification by ACAT2. The latter enzyme appears to be responsible for cholest erol ester formation and secretion in lipoproteins, whereas ACAT1 appears t o function to maintain appropriate cholesterol availability in cell membran es. Curr Opin Lipidol 12:121-127. (C) 2001 Lippincott Williams & Wilkins.