Mechanism of retarded liver regeneration in plasminogen activator-deficient mice: impaired activation of hepatocyte growth factor after Fas-mediated massive hepatic apoptosis

Hepatology. 2001 Mar;33(3):569-76. doi: 10.1053/jhep.2001.22650.


Urokinase-type plasminogen activator (uPA) is implicated in the regulation of hepatic regeneration by activating hepatocyte growth factor (HGF). Here, we investigated its role in the hepatic regeneration after Fas-mediated massive hepatocyte death employing mice deficient in either uPA or its inhibitor, plasminogen activator inhibitor-1 (PAI-1). We measured kinetics of hepatic levels of proliferating cell nuclear antigen (PCNA)-labeling index, plasmin activity, mature HGF, and its phosphorylated receptor, c-Met. In the genetically targeted and wild-type mice, hepatocytes fell into the same extent of apoptosis 6 to 12 hours after an intraperitoneal injection with anti-Fas antibody, as judged from histologic analysis and a histon-DNA enzyme-linked immunosorbent assay (ELISA). In the wild-type mice, mature HGF emerged in the liver 6 hours following anti-Fas injection, and hepatic PCNA-labeling index started to increase following 24 hours and peaked at 48 hours. In the uPA(-/-) mice, emergence of mature HGF was delayed 12 hours and hepatic regeneration peaked at 96 hours. Supplementation with the uPA gene to the uPA(-/-) mice by in vivo lipofection restored hepatic plasmin levels, and improved a delay in the expression of both mature HGF and phosphorylated c-Met, accompanying a normal rate of liver regeneration. In contrast, PAI-1(-/-) mice showed accelerated liver regeneration; mature HGF emerged as early as 3 hours, and PCNA-labeling index increased at 24 hours. This accelerated regeneration was abolished by administration with anti-HGF antibody. These results strongly suggest a physiologic role of uPA in the proteolytic maturation of HGF, and thereby in hepatic regeneration after Fas-mediated massive hepatocyte death.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Apoptosis / physiology*
  • DNA, Complementary / genetics
  • Hepatocyte Growth Factor / immunology
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / physiology*
  • Liver / pathology
  • Liver / physiopathology*
  • Liver Regeneration / drug effects
  • Liver Regeneration / physiology*
  • Male
  • Mice
  • Proliferating Cell Nuclear Antigen / metabolism
  • Transfection
  • Urokinase-Type Plasminogen Activator / deficiency
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / physiology*
  • fas Receptor / physiology*


  • Antibodies
  • DNA, Complementary
  • Proliferating Cell Nuclear Antigen
  • fas Receptor
  • Hepatocyte Growth Factor
  • Urokinase-Type Plasminogen Activator