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J. Biol. Chem., Vol. 279, Issue 45, 47402-47410, November 5, 2004
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in Mice Decreases Plasma High Density and Very Low Density Lipoproteins*
||**
From the
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada and the ¶Departments of Medicine, Anatomy and Cell Biology, and Physiology and Cellular Biophysics, Columbia University, New York, New York 10032
CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine. Hepatic cells express both an 
and a 
2 isoform of CT and can also synthesize phosphatidylcholine via the sequential methylation of phosphatidylethanolamine catalyzed by phosphatidylethanolamine N-methyltransferase. To ascertain the functional importance of CT, we created a mouse in which the hepatic CT gene was specifically inactivated by the Cre/LoxP procedure. In CT knockout mice, hepatic CT activity (due to residual CT2 activity as well as activity in nonhepatic cells) was 15% of normal, whereas phosphatidylethanolamine N-methyltransferase activity was elevated 2-fold compared with controls. Lipid analyses of the liver indicated that female knockout mice had reduced phosphatidylcholine levels and accumulated triacylglycerols. The plasma phosphatidylcholine concentration was reduced in the CT knockout (independent of gender), as were levels of high density lipoproteins (cholesterol and apoAI) and very low density lipoproteins (triacylglycerols and apoB100). Experiments in which mice were injected with Triton WR1339 indicated that apoB secretion was decreased in hepatic-specific CT knockout mice compared with controls. These results suggest an important role for hepatic CT in regulating both hepatic and systemic lipid and lipoprotein metabolism.
Received for publication, April 12, 2004 , and in revised form, August 23, 2004.
* This work was supported by grants from the Canadian Institutes of Health Research and National Institutes of Health Grant H:54591. 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 a Canadian Institutes of Health Research Postdoctoral Fellowship and an Alberta Heritage Foundation for Medical Research Postdoctoral Fellowship.
|| Holder of the Canada Research Chair in Molecular and Cell Biology of Lipids and Medical Scientist of the Alberta Heritage Foundation of Medical Research.
** To whom correspondence should be addressed. Tel.: 780-492-8286; Fax: 780-492-3383; E-mail: dennis.vance{at}ualberta.ca.
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