Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel

Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells.

Publication ,  Journal Article
Kohl, T; Gehrke, N; Schad, A; Nagel, M; Wörns, MA; Sprinzl, MF; Zimmermann, T; He, Y-W; Galle, PR; Schuchmann, M; Schattenberg, JM
Published in: Cell Death Dis
July 4, 2013

The endemic occurrence of obesity and the associated risk factors that constitute the metabolic syndrome have been predicted to lead to a dramatic increase in chronic liver disease. Non-alcoholic steatohepatitis (NASH) has become the most frequent liver disease in countries with a high prevalence of obesity. In addition, hepatic steatosis and insulin resistance have been implicated in disease progression of other liver diseases, including chronic viral hepatitis and hepatocellular carcinoma. The molecular mechanisms underlying the link between insulin signaling and hepatocellular injury are only partly understood. We have explored the role of the antiapoptotic caspase-8 homolog cellular FLICE-inhibitory protein (cFLIP) on liver cell survival in a diabetic model with hypoinsulinemic diabetes in order to delineate the role of insulin signaling on hepatocellular survival. cFLIP regulates cellular injury from apoptosis signaling pathways, and loss of cFLIP was previously shown to promote injury from activated TNF and CD95/Apo-1 receptors. In mice lacking cFLIP in hepatocytes (flip(-/-)), loss of insulin following streptozotocin treatment resulted in caspase- and c-Jun N-terminal kinase (JNK)-dependent liver injury after 21 days. Substitution of insulin, inhibition of JNK using the SP600125 compound in vivo or genetic deletion of the mitogen-activated protein kinase (MAPK)9 (JNK2) in all tissues abolished the injurious effect. Strikingly, the difference in injury between wild-type and cFLIP-deficient mice occurred only in vivo and was accompanied by liver-infiltrating inflammatory cells with a trend toward increased amounts of NK1.1-positive cells and secretion of proinflammatory cytokines. Transfer of bone marrow from rag-1-deficient mice that are depleted from B and T lymphocytes prevented liver injury in flip(-/-) mice. These findings support a direct role of insulin on cellular survival by alternating the activation of injurious MAPK, caspases and the recruitment of inflammatory cells to the liver. Thus, increasing resistance to insulin signaling pathways in hepatocytes appears to be an important factor in the initiation and progression of chronic liver disease.

Duke Scholars

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

July 4, 2013

Volume

4

Issue

7

Start / End Page

e712

Location

England

Related Subject Headings

  • Streptozocin
  • Sequence Homology, Amino Acid
  • Mitogen-Activated Protein Kinase 9
  • Mice, Knockout
  • Mice
  • MAP Kinase Signaling System
  • Lymphocytes
  • Liver
  • Insulin
  • Hepatocytes
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kohl, T., Gehrke, N., Schad, A., Nagel, M., Wörns, M. A., Sprinzl, M. F., … Schattenberg, J. M. (2013). Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells. Cell Death Dis, 4(7), e712. https://doi.org/10.1038/cddis.2013.228
Kohl, T., N. Gehrke, A. Schad, M. Nagel, M. A. Wörns, M. F. Sprinzl, T. Zimmermann, et al. “Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells.Cell Death Dis 4, no. 7 (July 4, 2013): e712. https://doi.org/10.1038/cddis.2013.228.
Kohl, T., et al. “Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells.Cell Death Dis, vol. 4, no. 7, July 2013, p. e712. Pubmed, doi:10.1038/cddis.2013.228.
Kohl T, Gehrke N, Schad A, Nagel M, Wörns MA, Sprinzl MF, Zimmermann T, He Y-W, Galle PR, Schuchmann M, Schattenberg JM. Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells. Cell Death Dis. 2013 Jul 4;4(7):e712.

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

July 4, 2013

Volume

4

Issue

7

Start / End Page

e712

Location

England

Related Subject Headings

  • Streptozocin
  • Sequence Homology, Amino Acid
  • Mitogen-Activated Protein Kinase 9
  • Mice, Knockout
  • Mice
  • MAP Kinase Signaling System
  • Lymphocytes
  • Liver
  • Insulin
  • Hepatocytes