These authors contributed equally to this work.
Growth arrest–specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury†
Article first published online: 20 AUG 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Volume 52, Issue 4, pages 1371–1379, October 2010
How to Cite
Llacuna, L., Bárcena, C., Bellido-Martín, L., Fernández, L., Stefanovic, M., Marí, M., García-Ruiz, C., Fernández-Checa, J. C., García de Frutos, P. and Morales, A. (2010), Growth arrest–specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury. Hepatology, 52: 1371–1379. doi: 10.1002/hep.23833
Potential conflict of interest: Nothing to report.
- Issue published online: 28 SEP 2010
- Article first published online: 20 AUG 2010
- Manuscript Accepted: 28 JUN 2010
- Manuscript Received: 9 FEB 2010
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, by the Instituto de Salud Carlos III and Ministry of Science and Innovation of Spain. Grant Numbers: FIS09/00056, FIS07/0193, SAF2009-11417, SAF2008-02199, SAF2006-06780, SAF2004-07539, BFU2007-61699/BFI)
- Research Center for Liver and Pancreatic Diseases. Grant Number: P50 AA 11999
- US National Institute on Alcohol Abuse and Alcoholism
Growth arrest–specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here we report an early increase in serum GAS6 levels after I/R exposure. Moreover, unlike wild-type (WT) mice, Gas6−/− mice were highly sensitive to partial hepatic I/R, with 90% of the mice dying within 12 hours of reperfusion because of massive hepatocellular injury. I/R induced early hepatic protein kinase B (AKT) phosphorylation in WT mice but not in Gas6−/− mice without significant changes in c-Jun N-terminal kinase phosphorylation or nuclear factor kappa B translocation, whereas hepatic interleukin-1β (IL-1β) and tumor necrosis factor (TNF) messenger RNA levels were higher in Gas6−/− mice versus WT mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes and thus protected them from hypoxia-induced cell death, whereas GAS6 diminished lipopolysaccharide-induced cytokine expression (IL-1β and TNF) in murine macrophages. Finally, recombinant GAS6 treatment in vivo not only rescued GAS6 knockout mice from severe I/R-induced liver damage but also attenuated hepatic damage in WT mice after I/R. Conclusion: Our data have revealed GAS6 to be a new player in liver I/R injury that is emerging as a potential therapeutic target for reducing postischemic hepatic damage. (HEPATOLOGY 2010;)