Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury.
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.


CONCLUSIONS
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.
Llacuna
Laura
L
Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer/Centre d'Investigació Biomèdica Esther Koplowitz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
Bárcena
Cristina
C
Bellido-Martín
Lola
L
Fernández
Laura
L
Stefanovic
Milica
M
Marí
Montserrat
M
García-Ruiz
Carmen
C
Fernández-Checa
José C
JC
García de Frutos
Pablo
P
Morales
Albert
A
D000818:Animals; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D048031:JNK Mitogen-Activated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000099255:Growth Arrest-Specific Protein 6