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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1689.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Acyl-Coenzyme A:Cholesterol Acyltransferase-2 (ACAT-2) Is Responsible for Elevated Intestinal ACAT Activity in Diabetic Rats

Masaharu Hori; Maki Satoh; Kohichiro Furukawa; Yu-ichiro Sakamoto; Hideki Hakamata; Yoshihiro Komohara; Motohiro Takeya; Yutaka Sasaki; Akira Miyazaki; Seikoh Horiuchi

From the Department of Medical Biochemistry (M.H., M.S., K.F., Y.S., H.H., A.M., S.H.), the First Department of Internal Medicine (M.H., Y.S.), and the Department of Cell Pathology (Y.K., M.T.), Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; the Department of Analytical Chemistry (H.H.), School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan; and the Department of Biochemistry (A.M.), Showa University School of Medicine, Tokyo, Japan.

Correspondence to Dr Seikoh Horiuchi, Department of Medical Biochemistry, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail horiuchi{at}gpo.kumamoto-u.ac.jp

Objective— Diabetes-induced dyslipidemia is seen in streptozotocin-induced diabetic rats. This is caused, in part, by elevated intestinal acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity. Because two ACAT isozymes (ACAT-1 and ACAT-2) were identified, in the present study we determined which ACAT isozyme was involved in the elevated intestinal ACAT activity in diabetic rats.

Methods and Results— We cloned a full-length cDNA of rat ACAT-2. Its overexpression in ACAT-deficient AC29 cells demonstrated that the ACAT activity is derived from the cloned cDNA, and a 45-kDa protein of rat ACAT-2 cross-reacts with an anti-human ACAT-2 antibody. The tissue distribution of rat ACAT-2 mRNA revealed its restricted expression to liver and small intestine. Immunohistochemical analyses using an anti-human ACAT-2 antibody demonstrated that ACAT-2 is localized in villus–crypt axis of rat small intestine. The intestinal ACAT activity in diabetic rats was significantly immunodepleted by an anti–ACAT-2 antibody but not by an anti–ACAT-1 antibody. Finally, intestinal ACAT-2 in diabetic rats significantly increased at both protein and mRNA levels as compared with that in control rats.

Conclusions— Our data demonstrate that ACAT-2 isozyme is responsible for the increased intestinal ACAT activity of diabetic rats, suggesting an important role of ACAT-2 for dyslipidemia in diabetic patients.

Diabetic rats exhibit dyslipidemia caused, in part, by elevated intestinal acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity. We determined which ACAT isozyme (ACAT-1 or ACAT-2) was involved in the elevated intestinal ACAT activity in diabetic rats. We demonstrated an important role of ACAT-2, implicating its involvement in dyslipidemia in diabetic patients.

Key Words: acyl-coenzyme A:cholesterol acyltransferase-2 • diabetic rats • diabetes-induced dyslipidemia • cholesterol absorption • atherosclerosis

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