AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation

A role for melatonin and trimetazidine cocktail

Mohamed Amine Zaouali, Eleonora Boncompagni, Russel J Reiter, Mohamed Bejaoui, Isabel Freitas, Eirini Pantazi, Emma Folch-Puy, Hassen Ben Abdennebi, Francisco A. Garcia-Gil, Joan Roselló-Catafau

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)65-78
Number of pages14
JournalJournal of Pineal Research
Volume55
Issue number1
DOIs
StatePublished - Aug 2013

Fingerprint

Trimetazidine
AMP-Activated Protein Kinases
Endoplasmic Reticulum Stress
Autophagy
Melatonin
Fatty Liver
Transplants
Liver
Reperfusion Injury
Cold Ischemia
Reperfusion
Wounds and Injuries
Bile
Liver Transplantation
Phosphorylation

Keywords

  • AMPK
  • Autophagy
  • Cold ischemia/reperfusion injury
  • ER stress
  • IGL-1 preservation solution
  • Melatonin
  • Steatotic liver
  • Trimetazidine

ASJC Scopus subject areas

  • Endocrinology

Cite this

AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation : A role for melatonin and trimetazidine cocktail. / Zaouali, Mohamed Amine; Boncompagni, Eleonora; Reiter, Russel J; Bejaoui, Mohamed; Freitas, Isabel; Pantazi, Eirini; Folch-Puy, Emma; Abdennebi, Hassen Ben; Garcia-Gil, Francisco A.; Roselló-Catafau, Joan.

In: Journal of Pineal Research, Vol. 55, No. 1, 08.2013, p. 65-78.

Research output: Contribution to journalArticle

Zaouali, MA, Boncompagni, E, Reiter, RJ, Bejaoui, M, Freitas, I, Pantazi, E, Folch-Puy, E, Abdennebi, HB, Garcia-Gil, FA & Roselló-Catafau, J 2013, 'AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation: A role for melatonin and trimetazidine cocktail', Journal of Pineal Research, vol. 55, no. 1, pp. 65-78. https://doi.org/10.1111/jpi.12051
Zaouali, Mohamed Amine ; Boncompagni, Eleonora ; Reiter, Russel J ; Bejaoui, Mohamed ; Freitas, Isabel ; Pantazi, Eirini ; Folch-Puy, Emma ; Abdennebi, Hassen Ben ; Garcia-Gil, Francisco A. ; Roselló-Catafau, Joan. / AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation : A role for melatonin and trimetazidine cocktail. In: Journal of Pineal Research. 2013 ; Vol. 55, No. 1. pp. 65-78.
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