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 language | English (US) |
|---|---|
| Pages (from-to) | 65-78 |
| Number of pages | 14 |
| Journal | Journal of Pineal Research |
| Volume | 55 |
| Issue number | 1 |
| DOIs | |
| State | Published - Aug 2013 |
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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 journal › Article
}
TY - JOUR
T1 - AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation
T2 - A role for melatonin and trimetazidine cocktail
AU - Zaouali, Mohamed Amine
AU - Boncompagni, Eleonora
AU - Reiter, Russel J
AU - Bejaoui, Mohamed
AU - Freitas, Isabel
AU - Pantazi, Eirini
AU - Folch-Puy, Emma
AU - Abdennebi, Hassen Ben
AU - Garcia-Gil, Francisco A.
AU - Roselló-Catafau, Joan
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - AMPK
KW - Autophagy
KW - Cold ischemia/reperfusion injury
KW - ER stress
KW - IGL-1 preservation solution
KW - Melatonin
KW - Steatotic liver
KW - Trimetazidine
UR - http://www.scopus.com/inward/record.url?scp=84885190019&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885190019&partnerID=8YFLogxK
U2 - 10.1111/jpi.12051
DO - 10.1111/jpi.12051
M3 - Article
VL - 55
SP - 65
EP - 78
JO - Journal of Pineal Research
JF - Journal of Pineal Research
SN - 0742-3098
IS - 1
ER -