In vivo hepatic HB-EGF gene transduction inhibits Fas-induced liver injury and induces liver regeneration in mice: a comparative study to HGF

J Hepatol. 2006 Jun;44(6):1046-54. doi: 10.1016/j.jhep.2005.10.027. Epub 2005 Dec 7.


Background/aims: It is unknown whether heparin-binding EGF-like growth factor (HB-EGF) can be a therapeutic agent, although previous studies suggested that HB-EGF might be a hepatotrophic factor. This study explores the potential of hepatic HB-EGF gene therapy in comparison with HGF.

Methods: Mice received an intraperitoneal injection of the agonistic anti-Fas antibody 72 h after an intravenous injection of either adenoviral vector (1x10(11) particles) expressing human HB-EGF (Ad.HB-EGF), human HGF (Ad.HGF) or no gene (Ad.dE1.3), and were sacrificed 24 or 36 h later to assess liver injury and regeneration.

Results: Exogenous HB-EGF was predominantly localized on the membrane, suggesting the initial synthesis of proHB-EGF in hepatocytes. The control Ad.dE1.3-treated mice represented remarkable increases in serum ALT and AST levels and histopathologically severe liver injuries with numerous apoptosis, but a limited number of mitogenic hepatocytes. In contrast, the liver injuries and apoptotic changes were significantly inhibited, but the mitogenic hepatocytes remarkably increased, in both the Ad.HB-EGF- and Ad.HGF-treated mice. More mitogenic hepatocytes and milder injuries were observed in the Ad.HB-EGF-treated mice.

Conclusions: HB-EGF has more potent protective and mitogenic effects for hepatocytes than HGF, at least for the present conditions. In vivo hepatic HB-EGF gene transduction is therapeutic for Fas-induced liver injury.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antibodies / pharmacology
  • Apoptosis / genetics
  • Cell Membrane / chemistry
  • Epidermal Growth Factor / analysis
  • Epidermal Growth Factor / genetics*
  • Genetic Therapy*
  • Heparin-binding EGF-like Growth Factor
  • Hepatocyte Growth Factor / therapeutic use
  • Intercellular Signaling Peptides and Proteins
  • Liver / enzymology
  • Liver Diseases / immunology
  • Liver Diseases / therapy*
  • Liver Regeneration / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Transduction, Genetic
  • fas Receptor / drug effects


  • Antibodies
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • fas Receptor
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor