Phosphatidylcholine homeostasis and liver failure.
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.
Li
Zhaoyu
Z
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Agellon
Luis B
LB
Vance
Dennis E
DE
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000378:metabolism; D004032:Diet; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D008099:Liver / Q000201:enzymology; D017093:Liver Failure / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010713:Phosphatidylcholines / Q000378:metabolism*; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D002794:Choline; D002797:Choline Kinase; D010713:Phosphatidylcholines; D050918:Phosphatidylethanolamine N-Methyltransferase; D010741:Phospholipases A; D012316:RNA Nucleotidyltransferases; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C020126:Ethanolamine-phosphate cytidylyltransferase