Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation

Rajat Singh, Yongjun Wang, Jörn M. Schattenberg, Youqing Xiang, Mark J. Czaja

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Sustained activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates the development and progression of experimental diet-induced nonalcoholic fatty liver disease (NAFLD). Delineating the mechanism of JNK overactivation in the setting of a fatty liver is therefore essential to understanding the pathophysiology of NAFLD. Both human and experimental NAFLD are associated with oxidative stress and resultant lipid peroxidation, which have been proposed to mediate the progression of this disease from simple steatosis to steatohepatitis. The ability of oxidants and the lipid peroxidation product 4-hydroxynonenal (HNE) to activate JNK signaling suggested that these two factors may act synergistically to trigger JNK overactivation. The effect of HNE on hepatocyte injury and JNK activation was therefore examined in cells under chronic oxidant stress from overexpression of the prooxidant enzyme cytochrome P450 2E1 (CYP2E1), which occurs in NAFLD. CYP2E1-generated oxidant stress sensitized a rat hepatocyte cell line to death from normally nontoxic concentrations of HNE. CYP2E1-overexpressing cells underwent a more profound depletion of glutathione (GSH) in response to HNE secondary to decreased γ-glutamylcysteine synthetase activity. GSH depletion led to overactivation of JNK/c-Jun signaling at the level of mitogen-activated protein kinase kinase 4 that induced cell death. Oxidant stress and the lipid peroxidation product HNE cause synergistic overactivation of the JNK/c-Jun signaling pathway in hepatocytes, demonstrating that HNE may not be just a passive biomarker of hepatic oxidant stress but rather an active mediator of hepatocellular injury through effects on JNK signaling.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume297
Issue number5
DOIs
StatePublished - Nov 2009

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JNK Mitogen-Activated Protein Kinases
Hepatocytes
Oxidative Stress
Oxidants
Cytochrome P-450 CYP2E1
Lipid Peroxidation
Fatty Liver
MAP Kinase Kinase 4
Glutamate-Cysteine Ligase
4-hydroxy-2-nonenal
Wounds and Injuries
Glutathione
Disease Progression
Cell Death
Biomarkers
Diet
Cell Line
Non-alcoholic Fatty Liver Disease
Liver
Enzymes

Keywords

  • Glutathione
  • Lipid peroxidation
  • Nonalcoholic fatty liver disease

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation. / Singh, Rajat; Wang, Yongjun; Schattenberg, Jörn M.; Xiang, Youqing; Czaja, Mark J.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 297, No. 5, 11.2009.

Research output: Contribution to journalArticle

Singh, Rajat ; Wang, Yongjun ; Schattenberg, Jörn M. ; Xiang, Youqing ; Czaja, Mark J. / Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2009 ; Vol. 297, No. 5.
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