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Bortezomib enhances fatty liver preservation in Institut George Lopez-1 solution through adenosine monophosphate activated protein kinase and Akt/mTOR pathways

Authors

  • Mohamed Bejaoui,

    1. Experimental Pathology Department, IIBB-CSIC, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain
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  • Mohamed Amine Zaouali,

    1. Experimental Pathology Department, IIBB-CSIC, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain
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  • Emma Folch-Puy,

    1. Experimental Pathology Department, IIBB-CSIC, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain
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  • Eirini Pantazi,

    1. Experimental Pathology Department, IIBB-CSIC, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain
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  • Fawzia Bardag-Gorce,

    1. David Geffen School of Medicine at UCLA, Department of Hematology, Los Angeles, CA, USA
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  • Teresa Carbonell,

    1. Department de Fisiología, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain
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  • Joan Oliva,

    1. David Geffen School of Medicine at UCLA, Department of Hematology, Los Angeles, CA, USA
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  • Antoni Rimola,

    1. Liver Unit, Hospital Clínic de Barcelona, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain
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  • Hassen Ben Abdennebi,

    1. Biologie et Anthropologie moléculaire appliquées au développement et à la santé (UR12ES11), Faculté de Pharmacie, Université de Monastir, Monastir, Tunisia
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  • Joan Roselló-Catafau

    Corresponding author
    1. Experimental Pathology Department, IIBB-CSIC, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain
    • Correspondence

      Joan Roselló-Catafau, Experimental Pathology Department, IIBB-CSIC, C/ Roselló 161, 7th floor, 08036 Barcelona, Spain.

      E-mail: jrcbam@iibb.csic.es

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Abstract

Objectives

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.

Key findings

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.

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