Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice.
OBJECTIVE
Non-alcoholic-fatty-liver disease (NAFLD) is part of the metabolic syndrome. The spectrum of NAFLD includes NASH (non-alcoholic steatohepatitis), which is characterised by progressive inflammation associated with oxidative stress and apoptosis, finally triggering liver cirrhosis and hepatocellular carcinoma. HGF (hepatocyte growth factor)/mesenchymal-epithelial transition factor (c-Met) receptor signalling is known to activate distinct intracellular pathways mediating among others anti-apoptotic properties to hepatocytes. Therefore, the aim was to characterise the role of c-Met during NASH development.


METHODS
Hepatocyte specific c-Met knockout mice (c-MetΔ(hepa)) using the cre-loxP system and wild type controls (c-Met(loxP/loxP)) were fed a methionine-choline deficient (MCD) diet.


RESULTS
MCD feeding triggered massive steatosis, decreased survival and higher transaminases in c-MetΔ(hepa) livers compared to c-Met(loxP/loxP). Gene array analysis demonstrated that genes involved in fatty acid metabolism were strongly upregulated in c-MetΔ(hepa) livers correlating with higher amounts of hepatic free fatty acids. Consequently, c-MetΔ(hepa) mice showed significantly more TUNEL positive cells and more superoxide anion production than c-Met(loxPloxP) animals. Additionally, c-MetΔ(hepa) livers showed significantly larger fractions of infiltrating neutrophils, macrophages, and cytotoxic T cells. These changes correlated with an enhanced progression of liver fibrosis as evidenced by higher collagen deposition in c-MetΔ(hepa) livers. As increased apoptosis was a prominent feature in c-MetΔ(hepa) livers, we generated c-Met/Casp8Δ(hepa) double knockout mice. In these animals compared to c-MetΔ(hepa) animals the increase in apoptosis could be reverted.


CONCLUSIONS
c-Met deletion in hepatocytes triggers NASH progression. A prominent mechanism is higher fatty acid accumulation and increased apoptosis, which in part can be reverted by blocking caspase 8.
Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany. Electronic address: dkroy@ukaachen.de.
Daniela C
DC
Kroy
Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany.
Fabienne
F
Schumacher
Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany.
Pierluigi
P
Ramadori
Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany.
Maximilian
M
Hatting
Institute of Nutrition, Friedrich-Schiller-University, Jena, 07743 Jena, Germany.
Ina
I
Bergheim
Institute of Pathology, RWTH Aachen University Hospital, 52074 Aachen, Germany.
Nikolaus
N
Gassler
Wageningen University, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen, The Netherlands.
Mark V
MV
Boekschoten
Wageningen University, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen, The Netherlands.
Michael
M
Müller
Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany.
Konrad L
KL
Streetz
Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany.
Christian
C
Trautwein
D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D002796:Choline Deficiency / Q000378:metabolism; D004032:Diet / Q000009:adverse effects / Q000379:methods; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008082:Lipotropic Agents / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D008715:Methionine / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*
D008082:Lipotropic Agents; D017228:Hepatocyte Growth Factor; D008715:Methionine; D019859:Proto-Oncogene Proteins c-met; D053181:Caspase 8
HGF; NASH; c-Met