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

肝素结合EGF样生长因子（Heparin-binding EGF-like growth factor, HB-EGF）是EGF生长因子家族的一员，可结合并刺激EGF受体（EGFR）和EerbB4。在此之前，我们证明了HB-EGF是在几种肝损伤的情况下被诱导的，并且还表明在小鼠中转基因表达HB-EGF在部分肝切除术后的肝再生过程中加速了肝细胞的增殖。然而，HB-EGF在肝毒素急性肝损伤中的作用尚不清楚。为了澄清这个问题，我们产生了肝脏特异性HB-EGF敲除（KO）小鼠。注射CCl4后24小时，与WT小鼠相比，KO小鼠ALT水平显著升高(5486+ 1961 IU/ l vs. 2275+ 656 IU/ l, p<0。05)，说明肝脏HB-EGF缺乏导致肝损伤加速。Western blotting也显示注射ccl4后48小时PCNA蛋白表达水平显著降低。与此相一致的是，注射CCl4后48和72小时，KO小鼠的BrdU阳性肝细胞数量低于WT小鼠。KO小鼠的肝脏再生受损与损伤肝脏中ERK1/ 2 MAP激酶活性降低有关。此外，HB-EGF显著抑制tnf α诱导的小鼠肝细胞凋亡，且呈剂量依赖性，提示HB-EGF可能具有抗凋亡作用。结论：我们目前的研究表明HB-EGF可能通过激活ERK1/ 2在急性肝损伤中发挥保护作用。

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.