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

@article{citeulike:6031327, 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(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. 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(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. 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.}, author = {Giebeler, Arne and Boekschoten, Mark V. and Klein, Christian and Borowiak, Malgorzata and Birchmeier, Carmen and Gassler, Nikolaus and Wasmuth, Hermann E. and M\"{u}ller, Michael and Trautwein, Christian and Streetz, Konrad L.}, citeulike-article-id = {6031327}, citeulike-linkout-0 = {http://dx.doi.org/10.1053/j.gastro.2009.01.068}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19208365}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19208365}, doi = {10.1053/j.gastro.2009.01.068}, issn = {1528-0012}, journal = {Gastroenterology}, keywords = {fibrosis, hgf, liver, met}, month = {July}, number = {1}, posted-at = {2009-10-29 06:05:29}, priority = {2}, title = {c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile duct ligation in mice.}, url = {http://dx.doi.org/10.1053/j.gastro.2009.01.068}, volume = {137}, year = {2009} }

TY - JOUR ID - citeulike:6031327 L3 - citeulike-article-id:6031327 N2 - 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(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. 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(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. 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. IS - 1 JF - Gastroenterology SN - 1528-0012 TI - c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile duct ligation in mice. VL - 137 KW - fibrosis KW - hgf KW - liver KW - met AU - Giebeler, Arne AU - Boekschoten, Mark AU - Klein, Christian AU - Borowiak, Malgorzata AU - Birchmeier, Carmen AU - Gassler, Nikolaus AU - Wasmuth, Hermann AU - Müller, Michael AU - Trautwein, Christian AU - Streetz, Konrad PY - 2009/07// UR - http://dx.doi.org/10.1053/j.gastro.2009.01.068 ER -