Loss of HB-EGF accelerates carbon tetrachloride induced liver injury in mice

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Heparin-binding EGF-like growth factor(HB-EGF) is a member of EGF family of growth factors that binds to and stimulates EGF receptors(EGFR) and EerbB4. Previously, we demonstrated that the HB-EGF was induced in response to several liver injuries and also showed that transgenic expression of HB-EGF in mice accelerated proliferation of hepaocyte during liver regeneration after partial hepatectomy. However, the role of HB-EGF in acute liver injury induced by hepatotoxin remains still unclear. To clarify this issue, we generated liver specific HB-EGF knockout(KO) mice. At 24 hours after CCl4 injection, KO mice showed significant increased ALT level compared with WT mice(5486+ 1961 IU/ l vs. 2275+ 656 IU/ l, p<0. 05), indicating that hepatic HB-EGF deficiency caused acceleration of liver injury. Western blotting also showed significant reduced expression level of PCNA protein at 48 hours after CCl4injection. Consistent with this, the number of BrdU positive hepatocytes in KO mice was lower than that in WT mice at 48 and 72 hours after CCl4 injection. This impaired liver regeneration in KO mice was associated with reduced activity of ERK1/ 2 MAP kinase in injured livers. Furthermore, HB-EGF significantly suppressed apoptosis of mouse hepaocyte cell lines induced by TNFαin a dose dependent manner, indicating the possible anti-apoptotic role of HB-EGF. Conclusion : Our current study demonstrated that HB-EGF might play a protective role during acute liver injury through ERK1/ 2 activation.