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J. Biol. Chem., Vol. 282, Issue 11, 8404-8413, March 16, 2007

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Genetically Altered Expression of Spermidine/Spermine N¹-Acetyltransferase Affects Fat Metabolism in Mice via Acetyl-CoA^*

Jason Jell¹, Salim Merali¹, Mary L. Hensen, Richard Mazurchuk^¶, Joseph A. Spernyak^¶, Paula Diegelman, Nicholas D. Kisiel, Carlos Barrero, Kristin K. Deeb, Leena Alhonen^||, Mulchand S. Patel^**, and Carl W. Porter²

From the Departments of Pharmacology and Therapeutics and ^¶Cancer Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, the Fels Institute and Biochemistry Department, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, ^||A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FI-70211 Kuopio, Finland, and the ^**Department of Biochemistry, State University of New York at Buffalo School of Medicine, Buffalo, New York 14214

The acetylating enzyme, spermidine/spermine N¹-acetyltransferase, participates in polyamine homeostasis by regulating polyamine export and catabolism. Previously, we reported that overexpression of the enzyme in cultured tumor cells and mice activates metabolic flux through the polyamine pathway and depletes the N¹-acetyltransferase coenzyme and fatty acid precursor, acetyl-CoA. Here, we investigate this possibility in spermidine/spermine N¹-acetyltransferase transgenic mice in which the enzyme is systemically overexpressed and in spermidine/spermine N¹-acetyltransferase knock-out mice. Tissues of the former were characterized by increased N¹-acetyltransferase activity, a marked elevation in tissue and urinary acetylated polyamines, a compensatory increase in polyamine biosynthetic enzyme activity, and an increase in metabolic flux through the polyamine pathway. These polyamine effects were accompanied by a decrease in white adipose acetyl- and malonyl-CoA pools, a major (20-fold) increase in glucose and palmitate oxidation, and a distinctly lean phenotype. In SSAT-ko mice, the opposite relationship between polyamine and fat metabolism was observed. In the absence of N¹-acetylation of polyamines, there was a shift in urinary and tissue polyamines indicative of a decline in metabolic flux. This was accompanied by an increase in white adipose acetyl- and malonyl-CoA pools, a decrease in adipose palmitate and glucose oxidation, and an accumulation of body fat. The latter was further exaggerated under a high fat diet, where knock-out mice gained twice as much weight as wild-type mice. A model is proposed whereby the expression status of spermidine/spermine N¹-acetyltransferase alters body fat accumulation by metabolically modulating tissue acetyl- and malonyl-CoA levels, thereby influencing fatty acid biosynthesis and oxidation.

Received for publication, November 2, 2006 , and in revised form, December 18, 2006.

^* This work was supported by National Institutes of Health (NIH) Grants CA-022153 and CA-076428 (to C. W. P.), Roswell Park Cancer Institute Core Grant CA016056, and NIH Predoctoral Training Grant CA-CA09072. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence and reprint requests should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263. Tel.: 716-845-3002; Fax: 716-845-2353; E-mail: carl.porter{at}roswellpark.org.

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