c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile duct ligation in mice.
OBJECTIVE
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.
Giebeler
Arne
A
Department of Medicine III, University Hospital Aachen, Aachen, Germany.
Boekschoten
Mark V
MV
Klein
Christian
C
Borowiak
Malgorzata
M
Birchmeier
Carmen
C
Gassler
Nikolaus
N
Wasmuth
Hermann E
HE
Müller
Michael
M
Trautwein
Christian
C
Streetz
Konrad L
KL
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D001651:Cholestasis, Extrahepatic / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D003135:Common Bile Duct / Q000601:surgery; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D020556:Neutrophil Infiltration; D020411:Oligonucleotide Array Sequence Analysis; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met