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J. Biol. Chem., Vol. 282, Issue 51, 37082-37090, December 21, 2007

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Hypermethylation of Fads2 and Altered Hepatic Fatty Acid and Phospholipid Metabolism in Mice with Hyperhomocysteinemia^*

Angela M. Devlin, Recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada¹, Ranji Singh², Rachel E. Wade, Sheila M. Innis, Teodoro Bottiglieri, and Steven R. Lentz^¶

From the Nutrition Research Program, Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver V6H 3N1, Canada, the Baylor Institute of Metabolic Disease, Dallas, Texas 75226, and the ^¶Department of Internal Medicine, University of Iowa Carver College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52246

Alterations in lipid metabolism may play a role in the vascular pathology associated with hyperhomocysteinemia (HHcy). Homocysteine is linked to lipid metabolism through the methionine cycle and the synthesis of phosphatidylcholine (PC) by phosphatidylethanolamine (PE) methyltransferase, which is responsible for the synthesis of 20–40% of liver PC. The goal of the present study was to determine if the reduced methylation capacity in HHcy is associated with alterations in liver phospholipid and fatty acid metabolism. Mice heterozygous for disruption of cystathionine β-synthase (Cbs^+/-) fed a diet to induce HHcy (HH diet) had higher (p < 0.001) plasma total homocysteine (30.8 ± 4.4 µM, mean ± S.E.) than C57BL/6 mice (Cbs^+/+) fed the HH diet (7.0 ± 1.1 µM) or Cbs^+/+ mice fed a control diet (2.3 ± 0.3 µM). Mild and moderate HHcy was accompanied by lower adenosylmethionine/adenosylhomocysteine ratios (p < 0.05), higher PE (p < 0.05) and PE/PC ratios (p < 0.01), lower PE methyltransferase activity (p < 0.001), and higher linoleic acid (p < 0.05) and lower arachidonic acid (p < 0.05) in PE. Mice with moderate HHcy also had higher linoleic acid and -linolenic acid (p < 0.05) and lower arachidonic acid and docosahexaenoic acid (p < 0.05) in liver PC. The first step in the desaturation and elongation of linoleic acid and linolenic acid to arachidonic acid and docosahexaenoic acid, respectively, is catalyzed by (6)-desaturase (encoded by Fads2). We found hypermethylation of the Fads2 promoter (p < 0.01), lower Fads2 mRNA (p < 0.05), and lower (6)-desaturase activity (p < 0.001) in liver from mice with HHcy. These findings suggest that methylation silencing of liver Fads2 expression and changes in liver fatty acids may contribute to the pathology of HHcy.

Received for publication, May 23, 2007 , and in revised form, October 9, 2007.

^* This work was supported in part by the American Heart Association Beginning Grant-In-Aid 0465315Z (to A. M. D.), by the Heart and Stroke Foundation of BC and Yukon Grant-In-Aid (to A. M. D.), and by the Office of Research and Development, United States Dept. of Veterans Affairs and National Institutes of Health Grants HL63943 and HL 62984 (to S. R. L.). 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.

² Supported by a Doctoral Research Award from the Heart and Stroke Foundation of Canada.

¹ To whom correspondence should be addressed: Nutrition Research Program, Dept. of Paediatrics, University of British Columbia, 4500 Oak St., Mailbox 65, Vancouver, BC V6H 3N1, Canada. Tel.: 604-875-2000 (ext. 5378); Fax: 604-875-3597; E-mail: angela.devlin{at}ubc.ca.

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