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J. Biol. Chem., Vol. 280, Issue 31, 28299-28305, August 5, 2005
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Physiological Regulation of Phospholipid Methylation Alters Plasma Homocysteine in Mice*
¶¶¶
From the
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Canada, the ||Department of Biochemistry, Memorial University of Newfoundland, St. John's, Canada, and the Department of Medicine, Columbia University, New York, New York 10032
Biological methylation reactions and homocysteine (Hcy) metabolism are intimately linked. In previous work, we have shown that phosphatidylethanolamine N-methyltransferase, an enzyme that methylates phosphatidylethanolamine to form phosphatidylcholine, plays a significant role in the regulation of plasma Hcy levels through an effect on methylation demand (Noga, A. A., Stead, L. M., Zhao, Y., Brosnan, M. E., Brosnan, J. T., and Vance, D. E. (2003) J. Biol. Chem. 278, 5952–5955). We have further investigated methylation demand and Hcy metabolism in liver-specific CTP:phosphocholine cytidylyltransferase-
(CT) knockout mice, since flux through the phosphatidylethanolamine N-methyltransferase pathway is increased 2-fold to meet hepatic demand for phosphatidylcholine. Our data show that plasma Hcy is elevated by 20–40% in mice lacking hepatic CT. CT-deficient hepatocytes secrete 40% more Hcy into the medium than do control hepatocytes. Liver activity of betaine:homocysteine methyltransferase and methionine adenosyltransferase are elevated in the knockout mice as a mechanism for maintaining normal hepatic S-adenosylmethionine and S-adenosylhomocysteine levels. These data suggest that phospholipid methylation in the liver is a major consumer of AdoMet and a significant source of plasma Hcy.
Received for publication, February 22, 2005 , and in revised form, May 31, 2005.
* This research is supported by grants from the Canadian Institute of Health Research, the Canadian Diabetes Association, and the National Institutes of Health. 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.
Recipient of postdoctoral fellowships from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research.
¶ These authors contributed equally to this work.
** Recipient of the K. M. Hunter/Canadian Institutes of Health Research Doctoral Award.
Senior Investigator of the Canadian Institutes of Health Research.
¶¶ Holder of the Canada Research Chair in Molecular and Cell Biology of Lipids and Heritage Scientist of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: 328 HMRC, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-8286; Fax: 780-492-3393; E-mail: dennis.vance{at}ualberta.ca.
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