JNK1 but not JNK2 promotes the development of steatohepatitis in mice

Jörn M. Schattenberg, Rajat Singh, Yongjun Wang, Jay H. Lefkowitch, Raina M. Rigoli, Philipp E. Scherer, Mark J. Czaja

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and varying degrees of necroinflammation. Although chronic oxidative stress, inflammatory cytokines, and insulin resistance have been implicated in the pathogenesis of NAFLD, the mechanisms that underlie the initiation and progression of this disease remain unknown. c-Jun N-terminal kinase (JNK) is activated by oxidants and cytokines and regulates hepatocellular injury and insulin resistance, suggesting that this kinase may mediate the development of steatohepatitis. The presence and function of JNK activation were therefore examined in the murine methionine- and choline-deficient (MCD) diet model of steatohepatitis. Activation of hepatic JNK, c-Jun, and AP-1 signaling occurred in parallel with the development of steatohepatitis in MCD diet-fed mice. Investigations in jnk1 and jnk2 knockout mice demonstrated that jnk1, but not jnk2, was critical for MCD diet-induced JNK activation. JNK promoted the development of steatohepatitis as MCD diet-fed jnk1 null mice had significantly reduced levels of hepatic triglyceride accumulation, inflammation, lipid peroxidation, liver injury, and apoptosis compared with wild-type and jnk2 -/- mice. Ablation of jnk1 led to an increase in serum adiponectin but had no effect on serum levels of tumor necrosis factor-α. In conclusion, JNK1 is responsible for JNK activation that promotes the development of steatohepatitis in the MCD diet model. These findings also provide additional support for the critical mechanistic involvement of JNK1 overactivation in conditions associated with insulin resistance and the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)163-172
Number of pages10
JournalHepatology
Volume43
Issue number1
DOIs
StatePublished - Jan 2006

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JNK Mitogen-Activated Protein Kinases
Fatty Liver
Choline
Methionine
Diet
Insulin Resistance
Liver
Cytokines
Adiponectin
Transcription Factor AP-1
Wounds and Injuries
Serum
Oxidants
Knockout Mice
Lipid Peroxidation
Disease Progression
Triglycerides
Oxidative Stress
Phosphotransferases
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Hepatology

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Schattenberg, J. M., Singh, R., Wang, Y., Lefkowitch, J. H., Rigoli, R. M., Scherer, P. E., & Czaja, M. J. (2006). JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology, 43(1), 163-172. https://doi.org/10.1002/hep.20999

JNK1 but not JNK2 promotes the development of steatohepatitis in mice. / Schattenberg, Jörn M.; Singh, Rajat; Wang, Yongjun; Lefkowitch, Jay H.; Rigoli, Raina M.; Scherer, Philipp E.; Czaja, Mark J.

In: Hepatology, Vol. 43, No. 1, 01.2006, p. 163-172.

Research output: Contribution to journalArticle

Schattenberg, JM, Singh, R, Wang, Y, Lefkowitch, JH, Rigoli, RM, Scherer, PE & Czaja, MJ 2006, 'JNK1 but not JNK2 promotes the development of steatohepatitis in mice', Hepatology, vol. 43, no. 1, pp. 163-172. https://doi.org/10.1002/hep.20999
Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology. 2006 Jan;43(1):163-172. https://doi.org/10.1002/hep.20999
Schattenberg, Jörn M. ; Singh, Rajat ; Wang, Yongjun ; Lefkowitch, Jay H. ; Rigoli, Raina M. ; Scherer, Philipp E. ; Czaja, Mark J. / JNK1 but not JNK2 promotes the development of steatohepatitis in mice. In: Hepatology. 2006 ; Vol. 43, No. 1. pp. 163-172.
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