Abstract
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 A(2), 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.
Highlights
PE N-methyltransferase (PEMT) is found in significant amounts only in the livers of animals and accounts for ϳ30% of hepatic PC biosynthesis (8 –10)
Biliary Secretion of PC Is Lethal in CD-PemtϪ/Ϫ Mice—To understand why complete choline deprivation is lethal, PemtϪ/Ϫ mice and Mdr2Ϫ/Ϫ/PemtϪ/Ϫ mice were fed a CD diet for 3 days
Because ϳ60% of hepatic PC is excreted via biliary secretion each day [26, 27], we conclude that the lethality of choline deprivation in PemtϪ/Ϫ mice emanates primarily from the rapid depletion of hepatic PC via biliary excretion
Summary
PEMT is found in significant amounts only in the livers of animals and accounts for ϳ30% of hepatic PC biosynthesis (8 –10). PEMT coupled to PC catabolism is the only pathway for endogenous choline biosynthesis in animals. Because livers from PemtϪ/Ϫ mice lose ϳ50% of their hepatic PC when fed a CD diet for 3 days [11], we speculated that the rapid liver failure in PemtϪ/Ϫ mice fed a CD diet was due to rapid depletion of hepatic PC by export into bile. To test this hypothesis we bred PemtϪ/Ϫ mice with mice lacking MDR2. A quantitatively important fate of hepatic PC is secretion into bile mediated by a PC-specific flippase, multiple drug-resistant protein 2 (MDR2 in mice, MDR3 in humans, called ABCB4), in hepatocyte canalicular membranes (Fig. 1A) [7]
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