title: The role of phosphatidylethanolamine methyltransferase in a mouse model of intrahepatic cholestasis.
abstract: Intrahepatic cholestasis eventually leads to liver failure. We report here a condition that decreases liver damage in intrahepatic cholestasis based on a mouse model that lacks multiple drug resistant protein 2 (ABCB4). We found that lack of phosphatidylethanolamine N-methyltransferase (PEMT) decreased liver damage in Abcb4(-/-) mice caused by exposure of the liver to excess bile acids. The protective effect was not related to hepatic ratio of phosphatidylcholine to phosphatidylethanolamine or the level of cholesterol. The decreased concentration of bile acids in liver was related to impaired re-absorption of bile acids in intestine and increased disposal of bile acids in feces in Abcb4(-/-)/Pemt(-/-) mice as compared to Abcb4(-/-) mice. PEMT deficiency affected intestinal Na(+) absorption resulting in an impaired Na(+) concentration gradient along the length of the small intestine and abnormal absorption of bile acids mediated by apical sodium-dependent bile acid transporter (ASBT). The findings of this study suggest that inhibition of PEMT and/or reduction of intestinal sodium concentration may be helpful in attenuating liver damage and prolonging hepatic function in intrahepatic cholestasis.
authors.affiliation: Department of Biochemistry and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Li
authors.forename: Luis B
authors.initials: LB
authors.lastname: Agellon
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000201:enzymology* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015151:Immunoblotting; D007421:Intestine, Small / Q000378:metabolism; D017093:Liver Failure / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000378:metabolism; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000502:physiology*; D010714:Phosphatidylethanolamines / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D010713:Phosphatidylcholines; D050918:Phosphatidylethanolamine N-Methyltransferase; D010714:Phosphatidylethanolamines; D012964:Sodium; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C483858:phosphatidylethanolamine; C502772:Cyp7a1 protein, mouse