The Role of a New Hepatocyte Growth Factor in Liver Regeneration

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A mouse serum hepatocyte growth-stimulating activity markedly increased 24 h after carbon tetrachloride administration and then decreased. This time course of the activity was paralled with those of serum alanine and aspartate aminotransferses activities. hepatocyte growth-stimulating activity in liver extracts was low in untreated mice, but increased after carbon tetrachloride. The increase was detectable 12 h and marked 24 h after the hepatotoxin. It was maximal 48 h after the administration and then dropped gradually. Liver DNA synthesis began to rise and was highest 36 h and 48 h, respectively, after the hepatotoxin. Thus, the hepatocyte growth-stimulating activity in serum and liver increased prior to liver regeneration in carbon tetrachloride-treated mice. The elevated serum and liver activities may play an important role in promoting proliferation of liver cells in vivo subsequent to hepatic injury. Mouse hepatocyte growth factor (mHGF) was purified about 280,000-fold with 21% yield form the liver supernatant of mice treated with the hepatotoxin by ammonium sulfate fractionation followed by chromatography on Affi-Gel Blue, heparin-Sepharose and S-Sepharose. SDS-PolyacrylAmide Gel Electrophoresis (PAGE) of purified mHGF under nonreducing conditions showed a single band with a Molecular Weight (MW) of 76K, while two bands with MWs of 62K and 31K were detected after SDS-PAGE of reduced mHGF, showing that mHGF is a heterodimer. mHGF stimulated DNA synthesis of cultured hepatocytes as effectively as hHGF. The effect of mHGF was additive with the maximal effects of EGF and acidic FGF and synergistic with that of insulin, but not with the maximal effect of hHGF. Thus, the properties of mHGF are similar to those of hHGF. mHGF may be a hHGF-like factor with some structural differences from hHGF, because the activity of mHGF was not inhibited by rabbit anti-hHGF antiserum which neutralizes the hHGF activity.