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

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 137; no. 1; p. 297
• Main Authors: Giebeler, Arne, Boekschoten, Mark V, Klein, Christian, Borowiak, Malgorzata, Birchmeier, Carmen, Gassler, Nikolaus, Wasmuth, Hermann E, Müller, Michael, Trautwein, Christian, Streetz, Konrad L
• Format: Journal Article
• Language: English
• Published: United States 01.07.2009
• Subjects: Animals; Apoptosis - genetics; Cell Proliferation; Cholestasis, Extrahepatic - complications; Cholestasis, Extrahepatic - genetics; Cholestasis, Extrahepatic - metabolism; Cholestasis, Extrahepatic - pathology; Chronic Disease; Common Bile Duct - surgery; Cytokines - metabolism; Disease Models, Animal; Disease Progression; Extracellular Matrix Proteins - metabolism; Gene Expression Profiling - methods; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatitis - metabolism; Hepatitis - pathology; Hepatocyte Growth Factor - metabolism; Hepatocytes - metabolism; Hepatocytes - pathology; Inflammation Mediators - metabolism; Ligation; Liver - metabolism; Liver - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Cirrhosis - prevention & control; Mice; Mice, Knockout; Necrosis; Neutrophil Infiltration; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-met - deficiency; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Time Factors
• ISSN: 1528-0012
• DOI: 10.1053/j.gastro.2009.01.068

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.