TNFR1 controls apoptosis and chronic liver disease in hepatocyte-specific IKKγ (Nemo) mice.

  • Anjana Singh (Creator)
  • Francisco J. Cubero (Creator)
  • Erawan Borkham-Kamphorst (Creator)
  • Yulia A. Nevzorova (Creator)
  • Malika Al Masaoudi (Creator)
  • Mark Boekschoten (Creator)
  • Nikolaus Gassler (Creator)
  • Ralf Weiskirchen (Creator)
  • Tom Luedde (Creator)
  • Mathias Heikenwalder (Creator)
  • Michael Muller (Creator)
  • Christian Liedtke (Creator)
  • Christian Trautwein (Creator)

Dataset

Description

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-ĸB essential modulator in hepatocytes (NemoΔhepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in NemoΔhepa mice. Therefore, we generated NemoΔhepa/TRAIL-/- and NemoΔhepa/TNFR1-/- animals and analyzed the progression of liver injury. NemoΔhepa/TRAIL-/- displayed a similar phenotype to NemoΔhepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in NemoΔhepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in NemoΔhepa and NemoΔhepa/TRAIL-/- mice while NemoΔhepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in NemoΔhepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice.
Date made available3 Sep 2014
PublisherWageningen University

Research Output

TNFR1 determines progression of chronic liver injury in the IKK gamma/Nemo genetic model

Cubero, F. J., Singh, A., Borkham-Kamphorst, E., Nevzorova, Y. A., Al Masaoudi, M., Haas, U., Boekschoten, M. V., Gassler, N., Weiskirchen, R., Muller, M., Liedtke, C. & Trautwein, C., 2013, In : Cell Death and Differentiation. 20, 11, p. 1580-1592

Research output: Contribution to journalArticleAcademicpeer-review

  • 20 Citations (Scopus)

    Cite this

    Singh, A. (Creator), Cubero, F. J. (Creator), Borkham-Kamphorst, E. (Creator), Nevzorova, Y. A. (Creator), Al Masaoudi, M. (Creator), Boekschoten, M. (Creator), Gassler, N. (Creator), Weiskirchen, R. (Creator), Luedde, T. (Creator), Heikenwalder, M. (Creator), Muller, M. (Creator), Liedtke, C. (Creator), Trautwein, C. (Creator) (3 Sep 2014). TNFR1 controls apoptosis and chronic liver disease in hepatocyte-specific IKKγ (Nemo) mice. Wageningen University.