Heparin-Binding EGF-Like Growth Factor: Hepatotrophic Factor in Liver Regeneration

Abstract

The role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) as a hepatotrophic factor in liver regeneration is discussed. HB-EGF is a member of the EGF family that binds to the EGF receptor (EGF-R) and is a potent mitogen for hepatocytes. Levels of HB-EGF mRNA were increased during rat liver regeneration, starting at an early phase (1.5h) after partial hepatectomy, well before the production of hepatic hepatocyte growth factor (HGF) or transforming growth factor-α (TGFα) mRNA. The induction of HB-EGF mRNA level was detected in non-parenchymal cells, mainly Kuppfer cells and sinusoidal endothelial cells, after partial hepatectomy but was negligible in the hepatocytes. Hepatic HB-EGF may play an important role in the early stages of liver regeneration after partial hepatectomy via a paracrine mechanism. HB-EGF also increases in the regenerating rat liver after injury from hepatotoxins such as CC14 and D-galactosamine. In addition, when mice were injected with exogenous HB-EGF, the labeling index in the liver after hHB-EGF injection was low but significantly increased compared to control mice, indicating that exogenous hHB-EGF stimulated DNA synthesis in hepatocytes in vivo. In human subjects, plasma HB-EGF levels increased, reaching maximal levels approximately 5–7 days after gross hepatectomy (lobectomy and segmentectomy). These results indicate that HB-EGF serves as a hepatotrophic factor in vivo.