title: Physiological roles of phosphatidylethanolamine N-methyltransferase.
abstract: Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes the methylation of phosphatidylethanolamine to phosphatidylcholine (PC). This 22.3 kDa protein is localized to the endoplasmic reticulum and mitochondria associated membranes of liver. The supply of the substrates AdoMet and phosphatidylethanolamine, and the product AdoHcy, can regulate the activity of PEMT. Estrogen has been identified as a positive activator, and Sp1 as a negative regulator, of transcription of the PEMT gene. Targeted inactivation of the PEMT gene produced mice that had a mild phenotype when fed a chow diet. However, when Pemt(-/-) mice were fed a choline-deficient diet steatohepatitis and liver failure developed after 3 days. The steatohepatitis was due to a decreased ratio of PC to phosphatidylethanolamine that caused leakage from the plasma membrane of hepatocytes. Pemt(-/-) mice exhibited attenuated secretion of very low-density lipoproteins and homocysteine. Pemt(-/-) mice bred with mice that lacked the low-density lipoprotein receptor, or apolipoprotein E were protected from high fat/high cholesterol-induced atherosclerosis. Surprisingly, Pemt(-/-) mice were protected from high fat diet-induced obesity and insulin resistance compared to wildtype mice. If the diet were supplemented with additional choline, the protection against obesity/insulin resistance in Pemt(-/-) mice was eliminated. Humans with a Val-to-Met substitution in PEMT at residue 175 may have increased susceptibility to nonalcoholic liver disease. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada. dennis.vance@ualberta.ca
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
mesh_terms: D000818:Animals; D002794:Choline / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D010713:Phosphatidylcholines / Q000378:metabolism; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics; D010714:Phosphatidylethanolamines / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D004967:Estrogens; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011973:Receptors, LDL; D016329:Sp1 Transcription Factor; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase; D002794:Choline