Devlin-2 - THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL 282 NO 51 pp 3708237090 Printed in the U.S.A Hypermethylation of Fads2 and Altered Hepatic Fatty

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Hypermethylation of Fads2 and Altered Hepatic Fatty Acid and Phospholipid Metabolism in Mice with Hyperhomocysteinemia * Received for publication, May 23, 2007, and in revised form, October 9, 2007 Published, JBC Papers in Press, October 30, 2007, DOI 10.1074/jbc.M704256200 Angela M. Devlin ‡1 , Ranji Singh ‡2 , 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 vas- cular pathology associated with hyperhomocysteinemia (HHcy). Homocysteine is linked to lipid metabolism through the methionine cycle and the synthesis of phosphatidylcho- line (PC) by phosphatidylethanolamine (PE) methyltrans- ferase, 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 ± -syn- thase ( Cbs ² / ³ ) fed a diet to induce HHcy (HH diet) had higher ( p < 0.001) plasma total homocysteine (30.8 ´ 4.4 µ M , mean ´ S.E.) than C57BL/6 mice ( Cbs ² / ² ) fed the HH diet (7.0 ´ 1.1 M )or Cbs ² / ² mice fed a control diet (2.3 ´ 0.3 M ). 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, respec- tively, 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)-desatu- rase 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. Elevation of plasma total homocysteine (tHcy) 3 is associated with increased risk for cardiovascular disease (1). The molecu- lar mechanisms contributing to the vasculopathies associated with hyperhomocysteinemia (HHcy), however, have not been fully characterized. Impaired endothelium-dependent vasodi- lation has been observed in human subjects with acute HHcy induced by oral methionine loading (2) and in animal models of diet-induced chronic HHcy (3). Mice with HHcy produced by heterozygosity for targeted disruption of the genes for cystathi- onine -synthase ( Cbs , EC 4.2.1.22), methylenetetrahydrofo- late reductase (EC 1.5.1.20), or methionine synthase (EC 2.1.1.13) have enhanced sensitivity to endothelial dysfunction
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Devlin-2 - THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL 282 NO 51 pp 3708237090 Printed in the U.S.A Hypermethylation of Fads2 and Altered Hepatic Fatty

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