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Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP.

Publication ,  Journal Article
Schattenberg, JM; Nagel, M; Kim, YO; Kohl, T; Wörns, MA; Zimmermann, T; Schad, A; Longerich, T; Schuppan, D; He, Y-W; Galle, PR; Schuchmann, M
Published in: Am J Physiol Gastrointest Liver Physiol
August 15, 2012

Chronic liver disease promotes hepatocellular injury involving apoptosis and triggers compensatory regeneration that leads to the activation of quiescent stellate cells in the liver. The deposition of extracellular matrix from activated myofibroblasts promotes hepatic fibrosis and the progression to cirrhosis with deleterious effects on liver physiology. The role of apoptosis signaling pathways in the development of fibrosis remains undefined. The aim of the current study was to determine the involvement of the caspase-8 homologue cellular FLICE-inhibitory protein (cFLIP) during the initiation and progression of fibrosis. Liver injury and fibrosis from carbon tetrachloride (CCl(4)) and thioacetamide (TAA) were examined in mice exhibiting a hepatocyte-specific deletion of cFLIP (flip(-/-)). Acute liver injury from CCl(4) and TAA were enhanced in flip(-/-) mice. This was accompanied by increased activation of caspase-3 and -9, pronounced phosphorylation of JNK, and decreased phosphorylation of Erk. Deletion of the cJun NH(2)-terminal kinase 2 (JNK2) in flip(-/-) mice protected from injury. Hepatic fibrosis was increased at baseline in 12-wk-old flip(-/-) mice, and progression of fibrosis from TAA was accelerated compared with the wild type. In conclusion, deletion of cFLIP in hepatocytes leads to increased fibrosis and accelerated fibrosis progression. This is accompanied by increased injury involving the activation of caspases and JNK2. Thus predisposition to liver injury involving increased hepatocellular apoptosis is a critical mediator of accelerated fibrogenesis, and prevention of liver injury will be a most important measure for patients with chronic liver disease.

Duke Scholars

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

August 15, 2012

Volume

303

Issue

4

Start / End Page

G498 / G506

Location

United States

Related Subject Headings

  • Time Factors
  • Thioacetamide
  • Signal Transduction
  • Phosphorylation
  • Phenotype
  • Mitogen-Activated Protein Kinase 9
  • Mice, Knockout
  • Mice
  • Male
  • Liver Cirrhosis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Schattenberg, J. M., Nagel, M., Kim, Y. O., Kohl, T., Wörns, M. A., Zimmermann, T., … Schuchmann, M. (2012). Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP. Am J Physiol Gastrointest Liver Physiol, 303(4), G498–G506. https://doi.org/10.1152/ajpgi.00525.2011
Schattenberg, Jörn M., Michael Nagel, Yong Ook Kim, Tobias Kohl, Marcus A. Wörns, Tim Zimmermann, Arno Schad, et al. “Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP.Am J Physiol Gastrointest Liver Physiol 303, no. 4 (August 15, 2012): G498–506. https://doi.org/10.1152/ajpgi.00525.2011.
Schattenberg JM, Nagel M, Kim YO, Kohl T, Wörns MA, Zimmermann T, et al. Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP. Am J Physiol Gastrointest Liver Physiol. 2012 Aug 15;303(4):G498–506.
Schattenberg, Jörn M., et al. “Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP.Am J Physiol Gastrointest Liver Physiol, vol. 303, no. 4, Aug. 2012, pp. G498–506. Pubmed, doi:10.1152/ajpgi.00525.2011.
Schattenberg JM, Nagel M, Kim YO, Kohl T, Wörns MA, Zimmermann T, Schad A, Longerich T, Schuppan D, He Y-W, Galle PR, Schuchmann M. Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP. Am J Physiol Gastrointest Liver Physiol. 2012 Aug 15;303(4):G498–G506.

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

August 15, 2012

Volume

303

Issue

4

Start / End Page

G498 / G506

Location

United States

Related Subject Headings

  • Time Factors
  • Thioacetamide
  • Signal Transduction
  • Phosphorylation
  • Phenotype
  • Mitogen-Activated Protein Kinase 9
  • Mice, Knockout
  • Mice
  • Male
  • Liver Cirrhosis