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J. Biol. Chem., Vol. 283, Issue 4, 2147-2155, January 25, 2008

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Hepatic CTP:Phosphocholine Cytidylyltransferase- Is a Critical Predictor of Plasma High Density Lipoprotein and Very Low Density Lipoprotein^*

René L. Jacobs¹, Susanne Lingrell, Yang Zhao, Gordon A. Francis², and Dennis E. Vance, Holder of the Canada Research Chair in Molecular and Cell Biology of Lipids and Scientist of the Alberta Heritage Foundation for Medical Research³

From the Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and the Departments of Biochemistry and Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

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 CT gene was specifically inactivated by the cre/loxP procedure. In CT 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 CT, apoAI-dependent PC efflux returned partially, whereas cholesterol efflux and ABCA1 levels were not restored to normal levels. Adenoviral expression of CT did not increase VLDL secretion in knock-out hepatocytes, even though cellular PC levels returned to normal. However, in vivo adenoviral delivery of CT 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.

Received for publication, August 9, 2007 , and in revised form, November 8, 2007.

^* This work was supported in part by Canadian Institutes of Health Research Grants MOP 62935 and MOP 12660. 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.

¹ Recipient of postdoctoral fellowships from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research.

² Senior Scholar of the Alberta Heritage Foundation for Medical Research.

³ To whom correspondence should be addressed: 328 HMRC, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-8286; Fax: 780-492-3383; E-mail: dennis.vance{at}ualberta.ca.

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