on July 8, 2004
Published online before print July 8, 2004, doi: 10.1161/01.ATV.0000137976.88533.13
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Submitted on May 16, 2004
Accepted on June 16, 2004
Acyl-Coenzyme A:Cholesterol Acyltransferase-2 (ACAT-2) Is Responsible for Elevated Intestinal ACAT Activity in Diabetic Rats
Masaharu Hori ;
From the Department of Medical Biochemistry (M.H., M.S., K.F., Y.-i.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, Showa, Japan.
* To whom correspondence should be addressed. E-mail: horiuchi{at}gpo.kumamoto-u.ac.jp.
Objective-- Streptozotocin-induced dyslipidemia can be seen in diabetic rats. This is caused, in part, by elevated intestinal acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity. Because 2 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 antihuman ACAT-2 antibody. The tissue distribution of rat ACAT-2 mRNA revealed its restricted expression to liver and small intestine. Immunohistochemical analyses using an antihuman 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 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.
Key words: acyl-coenzyme A:cholesterol acyltransferase-2 • diabetic rats • diabetes-induced dyslipidemia • cholesterol absorption • atherosclerosis
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