Deletion of Apoptosis Signal-Regulating Kinase 1 Attenuates Acetaminophen-Induced Liver Injury by Inhibiting c-Jun N-Terminal Kinase Activation

Hayato Nakagawa, Shin Maeda, Yohko Hikiba, Tomoya Ohmae, Wataru Shibata, Ayako Yanai, Kei Sakamoto, Keiji Ogura, Takuya Noguchi, Michael Karin, Hidenori Ichijo, Masao Omata

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Background & Aims: Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure. C-jun N-terminal kinase (JNK) is thought to play a central role in APAP-induced liver injury, although its upstream activator has not yet been identified. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family and is important for stress-induced JNK activation. We tested the hypothesis that ASK1 was involved in APAP-induced JNK activation and liver injury. Methods: ASK1-deficient (ASK1-/-) mice and wild-type (WT) mice were given 300 mg/kg of APAP. Serum alanine aminotransferase levels and liver histology were assessed. To investigate the involvement of ASK1 in direct hepatocellular damage and the subsequent inflammatory response, we used primary hepatocytes and splenocytes from WT and ASK1-/- mice. Results: In ASK1-/- mouse liver, APAP toxicity was attenuated significantly and the prolonged activation of JNK was inhibited. In addition, thioredoxin, a direct ASK1 inhibitor, dissociated from ASK1 after APAP overdose with concomitant ASK1 activation. Although the prolonged activation of p38 also was attenuated in ASK1-/- mice, the p38 signaling pathway was not likely to be involved in APAP-induced liver injury. Primary hepatocyte culture also revealed that ASK1 and JNK, but not p38, contributed to direct APAP-induced cellular damage. Conclusions: Our data suggest that ASK1 is activated by APAP overdose, most likely via a mechanism involving thioredoxin-ASK1 dissociation, and that it plays a role in APAP-induced liver injury through JNK activation.

Original languageEnglish
Pages (from-to)1311-1321
Number of pages11
JournalGastroenterology
Volume135
Issue number4
DOIs
Publication statusPublished - 2008 Oct
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Deletion of Apoptosis Signal-Regulating Kinase 1 Attenuates Acetaminophen-Induced Liver Injury by Inhibiting c-Jun N-Terminal Kinase Activation'. Together they form a unique fingerprint.

  • Cite this

    Nakagawa, H., Maeda, S., Hikiba, Y., Ohmae, T., Shibata, W., Yanai, A., Sakamoto, K., Ogura, K., Noguchi, T., Karin, M., Ichijo, H., & Omata, M. (2008). Deletion of Apoptosis Signal-Regulating Kinase 1 Attenuates Acetaminophen-Induced Liver Injury by Inhibiting c-Jun N-Terminal Kinase Activation. Gastroenterology, 135(4), 1311-1321. https://doi.org/10.1053/j.gastro.2008.07.006