title: Bortezomib enhances fatty liver preservation in Institut George Lopez-1 solution through adenosine monophosphate activated protein kinase and Akt/mTOR pathways.
abstract: OBJECTIVE
  The aim of this study is to investigate the protective mechanisms induced by bortezomib added to Institut George Lopez (IGL)-1 preservation solution to protect steatotic livers against cold ischaemia reperfusion injury and to examine whether these mechanisms occur through the activation of adenosine monophosphate activated protein kinase (AMPK), Akt/mTOR pathways.
  
  
  METHODS
  Steatotic livers from obese rats were preserved for 24 h (at 4 °C) in IGL-1 solution with or without bortezomib (100 nM) or pretreated with AMPK inhibitor adenine 9-α-D-arabinofuranoside and preserved in IGL-1 + bortezomib. Livers were then perfused for 2 h at 37 °C. Liver injury (alanine aminotransferase/aspartate aminotransferase) and function (bile production and vascular resistance) were measured. Also, Akt/mTOR, phosphorylated AMPK (pAMPK) and apoptosis were determined by Western blot analyses.
  
  
  RESULTS
  Bortezomib addition to IGL-1 solution significantly reduced steatotic liver injury, improved graft function and decreased liver apoptosis. These benefits were diminished by the pretreatment of obese rats with AMPK inhibitor Ara. Western blot analyses showed a significant increase in pAMPK after ischaemia and reperfusion. We also observed a significant phosphorylation of Akt in IGL-1 +bortezomib group that, in turn, induced the phosphorylation of mTOR and glycogen synthase kinase 3β.
  
  
  CONCLUSIONS
  Bortezomib, at low and non toxic concentration, is a promising additive to IGL-1 solution for steatotic liver preservation. Its protective effect is due to the activation of AMPK and Akt/mTOR pathways.
authors.affiliation: Experimental Pathology Department, IIBB-CSIC, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bejaoui
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.forename: Emma
authors.initials: E
authors.lastname: Folch-Puy
authors.forename: Eirini
authors.initials: E
authors.lastname: Pantazi
authors.forename: Fawzia
authors.initials: F
authors.lastname: Bardag-Gorce
authors.forename: Teresa
authors.initials: T
authors.lastname: Carbonell
authors.forename: Joan
authors.initials: J
authors.lastname: Oliva
authors.forename: Antoni
authors.initials: A
authors.lastname: Rimola
authors.forename: Hassen Ben
authors.initials: HB
authors.lastname: Abdennebi
authors.forename: Joan
authors.initials: J
authors.lastname: Roselló-Catafau
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D005234:Fatty Liver / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000378:metabolism; D012996:Solutions / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; C504757:IGL-1 solution; D019188:Organ Preservation Solutions; D011719:Pyrazines; D012996:Solutions; D000069286:Bortezomib; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; bortezomib; ischaemia reperfusion injury; liver preservation; steatosis