Impairment of activation of hepatocyte growth factor precursor into its mature form in rats with liver cirrhosis.

Abstract

BACKGROUND Hepatocyte growth factor (HGF) has a crucial role in liver regeneration following injury. The conversion of an inactive precursor form of HGF (proHGF) into a biologically active form (mature HGF) is essential, as HGF is involved in the recovery of liver damage. Liver regeneration is markedly poor in patients with liver cirrhosis after resection. We hypothesized that impairment of liver regeneration in cirrhosis is in part because of the absence of activation of proHGF to mature HGF. Studies were performed to clarify the molecular form of HGF in the liver of rats with fibrosis/cirrhosis before and after liver resection. METHODS Rat models of liver fibrosis/cirrhosis were induced by intraperitoneal administration of dimethylnitrosamine, followed by 45% partial hepatectomy or sham operation. HGF was purified from the liver and plasma on a SP-Sepharose column and was analyzed by Western blotting. RESULTS Production of proHGF in the liver increased in the following order: rats with normal liver, rats with fibrosis, and rats with cirrhosis. However, the levels of proHGF were similar after liver resection in the liver of these groups. A small but significant level of mature HGF was detected before resection in the fibrosis group, but not in the normal and cirrhosis groups. Liver resection increased the levels of mature HGF in the normal and fibrosis groups, but marginally in the cirrhosis group. CONCLUSIONS These results demonstrate that the conversion of proHGF into mature HGF is impaired after liver resection in liver cirrhosis, while proHGF production is similar in the livers of normal, fibrosis, and cirrhosis groups. Acceleration of the processing of the HGF molecule may contribute to the improvement of liver dysfunction in cirrhosis.