Hepatic CTP:phosphocholine cytidylyltransferase-alpha is a critical predictor of plasma high density lipoprotein and very low density lipoprotein.
CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine (PC). We previously generated a mouse in which the hepatic CTalpha gene was specifically inactivated by the cre/loxP procedure. In CTalpha knock-out mice, plasma high density lipoprotein (HDL) and very low density lipoprotein (VLDL) levels were markedly lower than in wild type mice (Jacobs, R. L., Devlin, C., Tabas, I., and Vance, D. E. (2004) J. Biol. Chem. 279, 47402-47410.) To investigate the mechanism(s) responsible for the decrease in plasma lipoprotein levels, we isolated primary hepatocytes from knock-out and wild type mice. ABCA1 expression was reduced in knock-out hepatocytes and apoAI-dependent cholesterol, and PC efflux was impaired. When knock-out hepatocytes were infected with an adenovirus expressing CTalpha, apoAI-dependent PC efflux returned partially, whereas cholesterol efflux and ABCA1 levels were not restored to normal levels. Adenoviral expression of CTalpha did not increase VLDL secretion in knock-out hepatocytes, even though cellular PC levels returned to normal. However, in vivo adenoviral delivery of CTalpha normalized plasma HDL and VLDL levels in knock-out mice. The observations demonstrate that hepatic PC biosynthesis is a key player in maintaining plasma VLDL and HDL, and further underscores the importance of the liver in HDL formation.
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
René L
RL
Jacobs
Susanne
S
Lingrell
Yang
Y
Zhao
Gordon A
GA
Francis
Dennis E
DE
Vance
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000256:Adenoviridae; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000097:blood / Q000235:genetics; D019916:Choline-Phosphate Cytidylyltransferase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology*; D008075:Lipoproteins, HDL / Q000097:blood* / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D014161:Transduction, Genetic
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D010713:Phosphatidylcholines; D002784:Cholesterol; D019916:Choline-Phosphate Cytidylyltransferase; C500611:Pcyt1a protein, mouse