Growth Arrest-Specific Protein 6 Is Hepatoprotective Against Murine ischemia/reperfusion Injury

Hepatology. 2010 Oct;52(4):1371-9. doi: 10.1002/hep.23833.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / therapeutic use*
  • Interleukin-1beta / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver Diseases / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / metabolism
  • Reperfusion Injury / prevention & control*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1beta
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • growth arrest-specific protein 6
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases