Bortezomib enhances fatty liver preservation in Institut George Lopez-1 solution through adenosine monophosphate activated protein kinase and Akt/mTOR pathways
Article first published online: 16 OCT 2013
© 2013 Royal Pharmaceutical Society
Journal of Pharmacy and Pharmacology
Volume 66, Issue 1, pages 62–72, January 2014
How to Cite
Bejaoui, M., Zaouali, M. A., Folch-Puy, E., Pantazi, E., Bardag-Gorce, F., Carbonell, T., Oliva, J., Rimola, A., Abdennebi, H. B. and Roselló-Catafau, J. (2014), Bortezomib enhances fatty liver preservation in Institut George Lopez-1 solution through adenosine monophosphate activated protein kinase and Akt/mTOR pathways. Journal of Pharmacy and Pharmacology, 66: 62–72. doi: 10.1111/jphp.12154
- Issue published online: 17 DEC 2013
- Article first published online: 16 OCT 2013
- Manuscript Accepted: 5 SEP 2013
- Manuscript Received: 16 MAR 2013
- Ministerio de Sanidad y Consumo. Grant Numbers: PI081988, PI12/00519
- Ciber-EHD, Instituto Carlos III, Madrid
- CSIC. Grant Number: ICOOP-0005 project
- ischaemia reperfusion injury;
- liver preservation;
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.
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.
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.
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.