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-MetΔhepa) 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-MetΔhepa mice. BDL in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-MetΔhepa mice revealed a significant reduction of anti-apoptotic genes in c-Met-deleted hepatocytes. These findings could be tested functionally because c-MetΔhepa 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-α 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-β1, α-smooth muscle actin, collagen-1α messenger RNA expression, and enhanced collagen-fiber staining in c-MetΔhepa 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. © 2009 AGA Institute.
CITATION STYLE
Giebeler, A., Boekschoten, M. V., Klein, C., Borowiak, M., Birchmeier, C., Gassler, N., … 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). https://doi.org/10.1053/j.gastro.2009.01.068
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