title: Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis.
abstract: Methionine adenosyltransferase 1A (MAT1A) and glycine N-methyltransferase (GNMT) are the primary genes involved in hepatic S-adenosylmethionine (SAMe) synthesis and degradation, respectively. Mat1a ablation in mice induces a decrease in hepatic SAMe, activation of lipogenesis, inhibition of triglyceride (TG) release, and steatosis. Gnmt-deficient mice, despite showing a large increase in hepatic SAMe, also develop steatosis. We hypothesized that as an adaptive response to hepatic SAMe accumulation, phosphatidylcholine (PC) synthesis by way of the phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway is stimulated in Gnmt(-/-) mice. We also propose that the excess PC thus generated is catabolized, leading to TG synthesis and steatosis by way of diglyceride (DG) generation. We observed that Gnmt(-/-) mice present with normal hepatic lipogenesis and increased TG release. We also observed that the flux from PE to PC is stimulated in the liver of Gnmt(-/-) mice and that this results in a reduction in PE content and a marked increase in DG and TG. Conversely, reduction of hepatic SAMe following the administration of a methionine-deficient diet reverted the flux from PE to PC of Gnmt(-/-) mice to that of wildtype animals and normalized DG and TG content preventing the development of steatosis. Gnmt(-/-) mice with an additional deletion of perilipin2, the predominant lipid droplet protein, maintain high SAMe levels, with a concurrent increased flux from PE to PC, but do not develop liver steatosis.
  
  
  CONCLUSIONS
  These findings indicate that excess SAMe reroutes PE towards PC and TG synthesis and lipid sequestration.
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Medical School, Bilbao, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Martínez-Uña
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.forename: Ainara
authors.initials: A
authors.lastname: Cano
authors.forename: Larraitz
authors.initials: L
authors.lastname: Fernández-Ares
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.forename: Igor
authors.initials: I
authors.lastname: Aurrekoetxea
authors.forename: Ibon
authors.initials: I
authors.lastname: Martínez-Arranz
authors.forename: Juan L
authors.initials: JL
authors.lastname: García-Rodríguez
authors.forename: Xabier
authors.initials: X
authors.lastname: Buqué
authors.forename: Daniela
authors.initials: D
authors.lastname: Mestre
authors.forename: Zigmund
authors.initials: Z
authors.lastname: Luka
authors.forename: Conrad
authors.initials: C
authors.lastname: Wagner
authors.forename: Cristina
authors.initials: C
authors.lastname: Alonso
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: M Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: Patricia
authors.initials: P
authors.lastname: Aspichueta
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D050938:Glycine N-Methyltransferase / Q000172:deficiency / Q000235:genetics; D006706:Homeostasis / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000070780:Perilipin-2; D010713:Phosphatidylcholines / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D000070780:Perilipin-2; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D014280:Triglycerides; C483858:phosphatidylethanolamine; D012436:S-Adenosylmethionine; D050938:Glycine N-Methyltransferase; C494511:Gnmt protein, mouse