title: Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline.
abstract: Choline is an essential nutrient for humans and is derived from the diet as well as from de novo synthesis involving methylation of phosphatidylethanolamine catalysed by the enzyme phosphatidylethanolamine N -methyltransferase (PEMT). This is the only known pathway that produces new choline molecules. We used mice with a disrupted Pemt-2 gene (which encodes PEMT; Pemt (-/-)) that have previously been shown to possess no hepatic PEMT enzyme. Male, female and pregnant Pemt (-/-) and wild-type mice ( n =5-6 per diet group) were fed diets of different choline content (deficient, control, and supplemented). Livers were collected and analysed for choline metabolites, steatosis, and apoptotic [terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling (TUNEL)] positive cells. We found that, in livers of Pemt (-/-) mice fed any of the diets, there was hepatic steatosis and significantly higher occurrence of TUNEL positive cells compared with wild-type controls. In male, female and pregnant mice, liver phosphatidylcholine concentrations were significantly decreased in Pemt (-/-) choline deficient and in Pemt (-/-) choline control groups but returned to normal in Pemt (-/-) choline supplemented groups. Phosphocholine concentrations in liver were significantly diminished in knockout mice even when choline was supplemented to above dietary requirements. These results show that PEMT normally supplies a significant portion of the daily choline requirement in the mouse and, when this pathway is knocked out, mice are unable to attain normal concentrations of all choline metabolites even with a supplemental source of dietary choline.
authors.affiliation: Department of Nutrition, CB #7461, School of Public Health, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7400, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhu
authors.forename: Jiannan
authors.initials: J
authors.lastname: Song
authors.forename: Mei-Heng
authors.initials: MH
authors.lastname: Mar
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Edwards
authors.forename: Steven H
authors.initials: SH
authors.lastname: Zeisel
mesh_terms: D000818:Animals; D017209:Apoptosis; D002794:Choline / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D053938:DNA Fragmentation; D004032:Diet; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050918:Phosphatidylethanolamine N-Methyltransferase; D011247:Pregnancy; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D008780:Methyltransferases; C494489:PEMT protein, human; D050918:Phosphatidylethanolamine N-Methyltransferase; D002794:Choline