title: AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: a role for melatonin and trimetazidine cocktail.
abstract: Ischemia/reperfusion injury (IRI) associated with liver transplantation plays an important role in the induction of graft injury. Prolonged cold storage remains a risk factor for liver graft outcome, especially when steatosis is present. Steatotic livers exhibit exacerbated endoplasmic reticulum (ER) stress that occurs in response to cold IRI. In addition, a defective liver autophagy correlates well with liver damage. Here, we evaluated the combined effect of melatonin and trimetazidine as additives to IGL-1 solution in the modulation of ER stress and autophagy in steatotic liver grafts through activation of AMPK. Steatotic livers were preserved for 24 hr (4°C) in UW or IGL-1 solutions with or without MEL + TMZ and subjected to 2-hr reperfusion (37°C). We assessed hepatic injury (ALT and AST) and function (bile production). We evaluated ER stress (GRP78, PERK, and CHOP) and autophagy (beclin-1, ATG7, LC3B, and P62). Steatotic livers preserved in IGL-1 + MEL + TMZ showed lower injury and better function as compared to those preserved in IGL-1 alone. IGL-1 + MEL + TMZ induced a significant decrease in GRP78, pPERK, and CHOP activation after reperfusion. This was consistent with a major activation of autophagic parameters (beclin-1, ATG7, and LC3B) and AMPK phosphorylation. The inhibition of AMPK induced an increase in ER stress and a significant reduction in autophagy. These data confirm the close relationship between AMPK activation and ER stress and autophagy after cold IRI. The addition of melatonin and TMZ to IGL-1 solution improved steatotic liver graft preservation through AMPK activation, which reduces ER stress and increases autophagy.
authors.affiliation: Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas, IDIBAPS-Ciberehd, Barcelona, Spain.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.forename: Eleonora
authors.initials: E
authors.lastname: Boncompagni
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bejaoui
authors.forename: Isabel
authors.initials: I
authors.lastname: Freitas
authors.forename: Eirini
authors.initials: E
authors.lastname: Pantazi
authors.forename: Emma
authors.initials: E
authors.lastname: Folch-Puy
authors.forename: Hassen Ben
authors.initials: HB
authors.lastname: Abdennebi
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Garcia-Gil
authors.forename: Joan
authors.initials: J
authors.lastname: Roselló-Catafau
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D006651:Histocytochemistry; D016031:Liver Transplantation; D008550:Melatonin / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000378:metabolism; D014292:Trimetazidine / Q000494:pharmacology*
chemical_list: D020011:Protective Agents; D055372:AMP-Activated Protein Kinases; D008550:Melatonin; D014292:Trimetazidine
keywords: AMPK; ER stress; IGL‐1 preservation solution; autophagy; cold ischemia/reperfusion injury; melatonin; steatotic liver; trimetazidine