The phosphatidylethanolamine N-methyltransferase pathway is quantitatively not essential for biliary phosphatidylcholine secretion

Henkjan J. Verkade¹^,*, Rick Havinga^*, David J. Shields²^,, Henk Wolters^*, Vincent W. Bloks^*, Folkert Kuipers^*, Dennis E. Vance and Luis B. Agellon

^* Pediatric Gastroenterology/Research Laboratory Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Canadian Institutes of Health Research Group on Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

Published, JLR Papers in Press, June 26, 2007.

^² Present address of D. J. Shields: Moores UCSD Cancer Center,3855 Health Sciences Drive, #0803, La Jolla, CA 92093-0803.

^¹ To whom correspondence should be addressed. e-mail: h.j.verkade{at}med.umcg.nl

The phosphatidylethanolamine N-methyltransferase (PEMT) pathwayof phosphatidylcholine (PC) biosynthesis is not essential forthe highly specific acyl chain composition of biliary PC. Weevaluated whether the PEMT pathway is quantitatively importantfor biliary PC secretion in mice under various experimentalconditions. Biliary bile salt and PC secretion were determinedin mice in which the gene encoding PEMT was inactivated (Pemt^–/–)and in wild-type mice under basal conditions, during acute metabolicstress (intravenous infusion of the bile salt tauroursodeoxycholate),and during chronic metabolic stress (feeding a taurocholate-containingdiet for 1 week). The activity of CTP:phosphocholine cytidylyltransferase,the rate-limiting enzyme of PC biosynthesis via the CDP-cholinepathway, and the abundance of multi-drug-resistant protein 2(Mdr2; encoded by the Abcb4 gene), the canalicular membraneflippase essential for biliary PC secretion, were determined.Under basal conditions, Pemt^–/– and wild-type miceexhibited similar biliary secretion rates of bile salt and PC( $~$ 145 and $~$ 28 nmol/min/100 g body weight, respectively). Duringacute or chronic bile salt administration, the biliary PC secretionrates increased similarly in Pemt^–/– and controlmice. Mdr2 mRNA and protein abundance did not differ betweenPemt^–/– and wild-type mice. The cytidylyltransferaseactivity in hepatic lysates was increased by 20% in Pemt^–/–mice fed the basal (bile salt-free) diet (P < 0.05). We concludethat the biosynthesis of PC via the PEMT pathway is not quantitativelyessential for biliary PC secretion under acute or chronic bilesalt administration.

Supplementary key words biliary lipids • bile salts • phosphatidylcholine biosynthesis • liver • cholesterol

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