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(Circulation. 2004;110:2017-2023.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

ACAT2 Is Localized to Hepatocytes and Is the Major Cholesterol-Esterifying Enzyme in Human Liver

Paolo Parini, MD, PhD; Matthew Davis, MS; Aaron T. Lada, PhD; Sandra K. Erickson, PhD; Teresa L. Wright, PhD; Ulf Gustafsson, MD; Staffan Sahlin, MD; Curt Einarsson, MD; Mats Eriksson, MD; Bo Angelin, MD; Hiroshi Tomoda, PhD; Satoshi mura, PhD; Mark C. Willingham, MD; Lawrence L. Rudel, PhD

From the Metabolism Unit (P.P., M.E., B.A.), Center for Metabolism and Endocrinology, Department of Medicine, and the Molecular Nutrition Unit, Center for Nutrition and Toxicology, Novum, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden; the Department of Pathology (P.F., M.D., A.T.L., M.C.W., L.L.R.), Wake Forest University School of Medicine, Winston-Salem, NC; the Department of Medicine and Liver Center (S.K.E., T.L.W.), University of California, and the Veterans Administration Medical Center, San Francisco, Calif; the Department of Surgery (U.G., S.S.), Karolinska Institute at Danderyd Hospital, Danderyd, Sweden; the Center for Gastroenterology (C.E.), Department of Medicine, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden; the Kitasato Institute for Life Sciences (H.T., S.O.), Kitasato University, Toyko, Japan; and the Department of Biochemistry (L.L.R.), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Lawrence L. Rudel, Department of Pathology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail lrudel{at}wfubmc.edu

Received January 23, 2004; revision received May 12, 2004; accepted May 21, 2004.

Background— Two acyl-coenzyme A:cholesterol acyltransferase (ACAT) genes, ACAT1 and ACAT2, have been identified that encode 2 proteins responsible for intracellular cholesterol esterification.

Methods and Results— In this study, immunohistology was used to establish their cellular localization in human liver biopsies. ACAT2 protein expression was confined to hepatocytes, whereas ACAT1 protein was found in Kupffer cells only. Studies with a highly specific ACAT2 inhibitor, pyripyropene A, in microsomal activity assays demonstrated that ACAT2 activity was highly variable among individual human liver samples, whereas ACAT1 activity was more similar in all specimens. ACAT2 provided the major cholesterol-esterifying activity in 3 of 4 human liver samples examined.

Conclusions— The data suggest that in diseases in which dysregulation of cholesterol metabolism occurs, such as hypercholesterolemia and atherosclerosis, ACAT2 should be considered a target for prevention and treatment.

Key Words: Key Words: • cholesterol • genes • lipids • metabolism

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