title: Acute liver injury induces nucleocytoplasmic redistribution of hepatic methionine metabolism enzymes.
abstract: OBJECTIVE
  The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease.
  
  
  RESULTS
  Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) α1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells.
  
  
  METHODS
  Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker.
  
  
  CONCLUSIONS
  Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of redox-dependent mechanisms in the control of MATα1 subcellular distribution.
authors.affiliation: 1 Departamento de Metabolismo y Señalización Celular, Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM) , Madrid, Spain .
authors.forename: Miguel
authors.initials: M
authors.lastname: Delgado
authors.forename: Francisco
authors.initials: F
authors.lastname: Garrido
authors.forename: Juliana
authors.initials: J
authors.lastname: Pérez-Miguelsanz
authors.forename: María
authors.initials: M
authors.lastname: Pacheco
authors.forename: Teresa
authors.initials: T
authors.lastname: Partearroyo
authors.forename: Dolores
authors.initials: D
authors.lastname: Pérez-Sala
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Pajares
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000208:Acute Disease; D043383:Adenosylhomocysteinase / Q000378:metabolism*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D005688:Galactosamine / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism*; D008716:Methionine Adenosyltransferase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
chemical_list: D000082:Acetaminophen; D005688:Galactosamine; D008715:Methionine; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; D043383:Adenosylhomocysteinase