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J. Biol. Chem., Vol. 280, Issue 45, 37798-37802, November 11, 2005

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Phosphatidylcholine Homeostasis and Liver Failure^*

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

In mammals, the only endogenous pathway for choline biosynthesis is the methylation of phosphatidylethanolamine to phosphatidylcholine (PC) by phosphatidylethanolamine N-methyltransferase (PEMT) coupled to PC degradation. Complete choline deprivation in mice by feeding Pemt^-/- mice a choline-deficient (CD) diet decreases hepatic PC by 50% and is lethal within 5 days. PC secretion into bile is mediated by a PC-specific flippase, multiple drug-resistant protein 2 (MDR2). Here, we report that mice that lack both PEMT and MDR2 and are fed a CD diet survive for >90 days. Unexpectedly, the amount of PC also decreases by 50% in the livers of Mdr2^-/-/Pemt^-/- mice. The Mdr2^-/-/Pemt^-/- mice adapt to the severe choline deprivation via choline recycling by induction of phospholipase A₂, choline kinase, and CTP:phosphocholine cytidylyltransferase activities and by a strikingly decreased expression of choline oxidase. The ability of Mdr2^-/-/Pemt^-/- mice to survive complete choline deprivation suggests that acute lethality in CD-Pemt^-/- mice results from rapid depletion of hepatic PC via biliary secretion.

Received for publication, August 4, 2005 , and in revised form, September 2, 2005.

^* This research was supported by grants from the Canadian Institutes of Health Research. 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 A Canadian Institutes of Health Research/Heart and Stroke Foundation of Canada Strategic Training Fellow in Stroke, Cardiovascular, Obesity, Lipids, and Atherosclerosis Research (SCOLAR) and supported by a grant from AstraZeneca.

² To whom correspondence should be addressed: Dept. of Biochemistry, 328 Heritage Medical Research Centre, 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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