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

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Item Type:	Article
Title:	c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile-duct-ligation in mice
Creators Name:	Giebeler, A., Boekschoten, M.V., Klein, C., Borowiak, M., Birchmeier, C., Gassler, N., Wasmuth, H.E., Mueller, M., Trautwein, C. and Streetz, K.L.
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.
Keywords:	Apoptosis, Cell Proliferation, Extrahepatic Cholestasis, Chronic Disease, Common Bile Duct, Cytokines, Animal Disease Models, Disease Progression, Extracellular Matrix Proteins, Gene Expression Profiling, Hepatic Stellate Cells, Hepatitis, Hepatocyte Growth Factor, Hepatocytes, Inflammation Mediators, Ligation, Liver, Liver Cirrhosis, Necrosis, Neutrophil Infiltration, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins c-met, Time Factors, Animals, Mice
Source:	Gastroenterology
ISSN:	0016-5085
Publisher:	Elsevier / Saunders
Volume:	137
Number:	1
Page Range:	297-308
Date:	July 2009
Official Publication:	https://doi.org/10.1053/j.gastro.2009.01.068
PubMed:	View item in PubMed

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