Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase α in mice decreases plasma high density and very low density lipoproteins

Abstract

CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CBP-choline pathway for the biosynthesis of phosphatidylcholine. Hepatic cells express both an αand a β2 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 CTα, we created a mouse in which the hepatic CTα gene was specifically inactivated by the Cre/LoxP procedure. In CTα knock-out mice, hepatic CT activity (due to residual CTβ2 activity as well as activity in nonhepatic cells) was 15% of normal, whereas phosphatidylethanolamine N-methyl-transferase 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 CTα 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 CTα knockout mice compared with controls. These results suggest an important role for hepatic CTα in regulating both hepatic and systemic lipid and lipoprotein metabolism.