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Papers In Press, published online ahead of print August 25, 2004
Biochemistry Dept., University of Alberta, Edmonton, Alberta T6G 2S2
Corresponding Author: dennis.vance{at}ualberta.ca
CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine. Hepatic cells express both an a and a ß2 isoform of CT, and can also synthesize phosphatidylcholine via the sequential methylation of phosphatidylethanolamine catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). To ascertain the functional importance of CTa, we created a mouse in which the hepatic CTa gene was specifically inactivated by the cre/loxP procedure. In CTa knockout mice, hepatic CT activity (due to residual CTß2 activity as well as activity in non-hepatic cells) was 15% of normal, while PEMT activity was elevated 2-fold compared to 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 CTa knockout (independent of gender), as were levels of high density lipoproteins (cholesterol and apo AI) and very low density lipoproteins (triacylglycerols and apo B100). Experiments in which mice were injected with Triton WR1339 indicated that apo B secretion was decreased in hepatic-specific CTa knockout mice compared to controls. These results suggest an important role for hepatic CTa in regulating both hepatic and systemic lipid and lipoprotein metabolism.
J. Biol. Chem, 10.1074/jbc.M404027200
Submitted on April 12, 2004
Revised on August 23, 2004
Accepted on August 25, 2004
Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase a in mice decreases plasma high density and very low density lipoproteins
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