Open Access

Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms

  • Authors:
    • Kouichi Sakamoto
    • Ngin Cin Khai
    • Yuqing Wang
    • Rie Irie
    • Hideo Takamatsu
    • Hiroshi Matsufuji
    • Ken-Ichiro Kosai
  • View Affiliations

  • Published online on: October 20, 2016     https://doi.org/10.3892/ijmm.2016.2784
  • Pages: 1673-1682
  • Copyright: © Sakamoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

In contrast to hepatocyte growth factor (HGF), the therapeutic potential and pathophysiologic roles of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver diseases remain relatively unknown. To address the lack of effective pharmacologic treatments for cholestatic liver injuries, as well as to clarify the biologic features of these growth factors, we explored the effects of HB-EGF and HGF in mice with cholestatic liver injury induced by bile duct ligation (BDL). The mice were assessed 3, 5 and/or 14 days after BDL (acute, subacute and/or chronic phases, respectively) and intravenous injection of adenoviral vector expressing LacZ (control), HB-EGF, HGF, or HB-EGF and HGF. HB-EGF, HGF, or a combination of the growth factors exerted potent antioncotic (antinecrotic), antiapoptotic, anticholestatic, and regenerative effects on hepatocytes in vivo, whereas no robust antiapoptotic or regenerative effects were detected in interlobular bile ducts. Based on serum transaminase levels, the acute protective effects of HB-EGF on hepatocytes were greater than those of HGF. On the other hand, liver fibrosis and cholestasis during the chronic phase were more potently inhibited by HGF compared with HB-EGF. Compared with either growth factor alone, combining HB-EGF and HGF produced greater anticholestatic and regenerative effects during the chronic phase. Taken together, these findings suggest that HB-EGF and HGF inhibited BDL-induced cholestatic liver injury, predominantly by exerting acute cytoprotective and chronic antifibrotic effects, respectively; combining the growth factors enhanced the anticholestatic effects and liver regeneration during the chronic phase. Our results contribute to a better understanding of the pathophysiologic roles of HB-EGF and HGF, as well as to the development of novel effective therapies for cholestatic liver injuries.
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December-2016
Volume 38 Issue 6

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Sakamoto K, Khai NC, Wang Y, Irie R, Takamatsu H, Matsufuji H and Kosai K: Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms. Int J Mol Med 38: 1673-1682, 2016
APA
Sakamoto, K., Khai, N.C., Wang, Y., Irie, R., Takamatsu, H., Matsufuji, H., & Kosai, K. (2016). Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms. International Journal of Molecular Medicine, 38, 1673-1682. https://doi.org/10.3892/ijmm.2016.2784
MLA
Sakamoto, K., Khai, N. C., Wang, Y., Irie, R., Takamatsu, H., Matsufuji, H., Kosai, K."Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms". International Journal of Molecular Medicine 38.6 (2016): 1673-1682.
Chicago
Sakamoto, K., Khai, N. C., Wang, Y., Irie, R., Takamatsu, H., Matsufuji, H., Kosai, K."Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms". International Journal of Molecular Medicine 38, no. 6 (2016): 1673-1682. https://doi.org/10.3892/ijmm.2016.2784