c-Met Confers Protection Against Chronic Liver Tissue Damage and Fibrosis Progression After Bile Duct Ligation in Mice.

A. Giebeler, M.V. Boekschoten, C. Klein, M. Borowiak, C. Birchmeier, N. Gassler, H.E. Wasmuth, M.R. Müller, C. Trautwein, K.L. Streetz

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53 Citations (Scopus)

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¿hepa) 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¿hepa mice. BDL in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-Met¿hepa mice revealed a significant reduction of anti-apoptotic genes in c-Met¿deleted hepatocytes. These findings could be tested functionally because c-Met¿hepa 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-¿ 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-ß1, ¿-smooth muscle actin, collagen-1¿ messenger RNA expression, and enhanced collagen-fiber staining in c-Met¿hepa 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.
Original languageEnglish
Pages (from-to)297-308
JournalGastroenterology
Volume137
Issue number1
DOIs
Publication statusPublished - 2009

Keywords

  • hepatocyte growth-factor
  • cre recombinase
  • hepatic-injury
  • nemo/ikk-gamma
  • cxc chemokines
  • expression
  • regeneration
  • cells
  • mouse
  • receptor

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

    Giebeler, A. (Creator), Klein, C. (Creator), Boekschoten, M. (Creator), Borowiak, M. (Creator), Birchmeier, C. (Creator), Gassler, N. (Creator), Muller, M. (Creator), Trautwein, C. (Creator) & Streetz, K. L. (Creator), Wageningen University, 18 Feb 2009

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    Cite this

    Giebeler, A., Boekschoten, M. V., Klein, C., Borowiak, M., Birchmeier, C., Gassler, N., Wasmuth, H. E., Müller, M. R., Trautwein, C., & Streetz, K. L. (2009). c-Met Confers Protection Against Chronic Liver Tissue Damage and Fibrosis Progression After Bile Duct Ligation in Mice. Gastroenterology, 137(1), 297-308. https://doi.org/10.1053/j.gastro.2009.01.068