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c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile-duct-ligation in mice

Authors

  • A. Giebeler
  • M.V. Boekschoten
  • C. Klein
  • M. Borowiak
  • C. Birchmeier
  • N. Gassler
  • H.E. Wasmuth
  • M. Mueller
  • C. Trautwein
  • K.L. Streetz

Journal

  • Gastroenterology

Citation

  • Gastroenterology 137 (1): 297-308

Abstract

  • BACKGROUND & AIMS: The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF receptor c-Met has been shown in acute liver regeneration, its cell-specific role in hepatocytes during chronic liver injury and fibrosis progression has not been determined. METHODS: Hepatocyte-specific c-Met knockout mice (c-Met(Deltahepa)) using the Cre-loxP system were studied in a bile duct ligation (BDL) model. Microarray analyses were performed to define HGF/c-Met-dependent gene expression. RESULTS: Two strategies for c-Met deletion in hepatocytes to generate hepatocyte-specific c-Met knockout mice were tested. Early deletion during embryonic development was lethal, whereas post-natal Cre expression was successful, leading to the generation of viable c-Met(Deltahepa) mice. BDL in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-Met(Deltahepa) mice revealed a significant reduction of anti-apoptotic genes in c-Met-deleted hepatocytes. These findings could be tested functionally because c-Met(Deltahepa) mice showed a stronger apoptotic response after BDL and Jo-2 stimulation. The phenotype was associated with increased expression of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger profibrogenic response as evidenced by increased transforming growth factor-beta(1), alpha-smooth muscle actin, collagen-1alpha messenger RNA expression, and enhanced collagen-fiber staining in c-Met(Deltahepa) mice. CONCLUSIONS: Our results show that deletion of c-Met in hepatocytes leads to more liver cell damage and fibrosis in a chronic cholestatic liver injury model because c-Met triggers survival signals important for hepatocyte recovery.


DOI

doi:10.1053/j.gastro.2009.01.068