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Gastroenterology. 2009 Jul;137(1):297-308, 308.e1-4. doi: 10.1053/j.gastro.2009.01.068. Epub 2009 Feb 5.

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

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Department of Medicine III, University Hospital Aachen, Aachen, Germany.



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.


Hepatocyte-specific c-Met knockout mice (c-Met(Delta 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.


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(Delta hepa) mice. BDL in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-Met(Delta hepa) mice revealed a significant reduction of anti-apoptotic genes in c-Met-deleted hepatocytes. These findings could be tested functionally because c-Met(Delta 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-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(Delta hepa) mice.


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.

[Indexed for MEDLINE]

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