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J Hepatol. 2014 Oct;61(4):883-90. doi: 10.1016/j.jhep.2014.05.019. Epub 2014 May 15.

Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice.

Author information

  • 1Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany. Electronic address:
  • 2Department of Medicine 3, RWTH Aachen University Hospital, 52074 Aachen, Germany.
  • 3Institute of Nutrition, Friedrich-Schiller-University, Jena, 07743 Jena, Germany.
  • 4Institute of Pathology, RWTH Aachen University Hospital, 52074 Aachen, Germany.
  • 5Wageningen University, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen, The Netherlands.



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.


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.


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.


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.

Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


HGF; NASH; c-Met

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