Background: Despite the improvement in organ preservation, the 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, an increase of ER stress is well correlated with defective liver autophagy. Here we evaluated the combined effect of melatonin (MEL) and trimetazidine (TMZ) as additive to Institute Georges Lopez-1 (IGL-1) preservation solutions in the modulation of ER stress and autophagy in steatotic liver grafts Experimental: Steatotic livers were preserved for 24 hr (4ºC) in UW or IGL-1 solutions with or without MEL+TMZ and subjected to 2-hr reperfusion (37ºC). We assessed hepatic injury (ALT and AST) and function (bile production). We evaluated ER stress by measuring changes of the levels of expression of the glucose-regulated protein 78 (GRP78), the RNA activated protein kinase (PKR)-like ER kinase (PERK) and CCAAT/enhancer-binding protein homologous protein (CHOP). We furthermore investigated other factors associated with autophagy: bcl-2-interacting partner (Beclin-1), autophagy-related protein 7 (ATG7) and microtubule-associated proteins 1A/1B light chain 3B (LC3B). Results:We demonstrated that steatotic livers preserved in IGL-1 enriched with MEL+TMZ showed lower injury and better function when compared to those preserved in IGL-1 alone. The preservation of fatty livers in IGL-1+MEL +TMZ induced a significant decrease in GRP78, pPERK and CHOP activation after 2-hr reperfusion. This was consistent with a major activation of autophagic parameters (Beclin-1, ATG7 and LC3B) and adenosine monophosphate protein kinase (AMPK) phosphorylation. The inhibition of AMPK induced an increase in ER stress and a significant decrease in autophagy. These data confirm the close relationship between AMPK activation and ER stress and autophagy after cold IRI. Conclusion: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.

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