Physiological regulation of phospholipid methylation alters plasma homocysteine in mice.
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-alpha (CTalpha) 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 CTalpha. CTalpha-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.
Jacobs
René L
RL
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Canada.
Stead
Lori M
LM
Devlin
Cecilia
C
Tabas
Ira
I
Brosnan
Margaret E
ME
Brosnan
John T
JT
Vance
Dennis E
DE
D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase; D002462:Cell Membrane / Q000378:metabolism; D003566:Cytidine Diphosphate Choline / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006710:Homocysteine / Q000097:blood*; D008099:Liver / Q000196:embryology; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*
D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D006710:Homocysteine; C483858:phosphatidylethanolamine; D003566:Cytidine Diphosphate Choline; D008780:Methyltransferases; D050940:Betaine-Homocysteine S-Methyltransferase; C494549:Bhmt protein, mouse; D008716:Methionine Adenosyltransferase