Targeted deletion of hepatic CTP:phosphocholine cytidylyltransferase alpha in mice decreases plasma high density and very low density lipoproteins.
CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine. Hepatic cells express both an alpha and a beta2 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 CTalpha, we created a mouse in which the hepatic CTalpha gene was specifically inactivated by the Cre/LoxP procedure. In CTalpha knockout mice, hepatic CT activity (due to residual CTbeta2 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 CTalpha 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 CTalpha knockout mice compared with controls. These results suggest an important role for hepatic CTalpha in regulating both hepatic and systemic lipid and lipoprotein metabolism.
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
René L
RL
Jacobs
Cecilia
C
Devlin
Ira
I
Tabas
Dennis E
DE
Vance
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D019916:Choline-Phosphate Cytidylyltransferase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D003902:Detergents / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D015151:Immunoblotting; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000494:pharmacology; D020033:Protein Isoforms; D012737:Sex Factors; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D001055:Apolipoproteins B; D002788:Cholesterol Esters; D003902:Detergents; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010713:Phosphatidylcholines; D020033:Protein Isoforms; D014280:Triglycerides; D011092:Polyethylene Glycols; D002784:Cholesterol; D019916:Choline-Phosphate Cytidylyltransferase; C016811:tyloxapol