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

doi:10.1053/j.gastro.2008.07.006

Gastroenterology

Volume 135, Issue 4, October 2008, Pages 1311-1321

https://doi.org/10.1053/j.gastro.2008.07.006 Get rights and content

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.

Section snippets

Animals

The generation of ASK1^−/−, JNK1^−/−, JNK2^−/−, and p38α^+/– mice has been described previously.22, 23, 24 All mice were back-crossed into the C57BL/6 strain at least 6 times. Male ASK1^−/−, JNK1^−/−, JNK2^−/−, and p38α^+/− mice, 8–10 weeks old, and appropriate age-matched male C57BL/6 wild-type mice (WT; Clea Japan, Tokyo, Japan) were used in all experiments.

The study design and protocols were approved by our institutional ethics committee for animal experimentation. All experiments were conducted in

Both JNK and ASK1 Are Involved in APAP-Induced Liver Injury

A single intraperitoneal injection of APAP (300 mg/kg) induced significant liver injury and marked increases in serum alanine aminotransferase (ALT) levels at 6 hours, peaking at 24 hours, in WT mice. To determine the role of ASK1 in APAP-induced liver injury, ASK1^−/− and WT mice were given 300 mg/kg APAP and killed at 6 and 24 hours posttreatment. The increase of serum ALT levels at 6 and 24 hours posttreatment were reduced significantly in ASK1^−/− mice compared with WT mice (Figure 1A) The

Discussion

Recent studies have reported that ASK1 is involved in the pathogenesis of various human diseases, including neurodegenerative³⁷ and cardiovascular³⁸ diseases. However, very little information is available regarding ASK1 and liver disease.³⁹ This report shows the involvement of ASK1 in an in vivo liver disease model.

We showed that the ASK1–JNK pathway plays an important role in APAP-induced liver injury. In ASK1^−/− mouse liver, APAP-induced prolonged JNK activation and liver injury was

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: S.M. and M.O. were supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#17209026 and #19390205).

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Basic—Liver, Pancreas, and Biliary TractDeletion of Apoptosis Signal-Regulating Kinase 1 Attenuates Acetaminophen-Induced Liver Injury by Inhibiting c-Jun N-Terminal Kinase Activation

Section snippets

Animals

Both JNK and ASK1 Are Involved in APAP-Induced Liver Injury

Discussion

Biochem Biophys Res Commun

J Biol Chem

Toxicol Appl Pharmacol

Gastroenterology

Gastroenterology

Cell

J Biol Chem

J Biol Chem

Hepatology

Mol Cell

Cell

Cell

Immunity

Hepatology

Gastroenterology

Semin Cancer Biol

J Biol Chem

J Biol Chem

J Biol Chem

Acetaminophen toxicity: changing perceptions on a social/medical issue

Hepatology

N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen

Proc Natl Acad Sci U S A

Protein targets of xenobiotic reactive intermediates

Annu Rev Pharmacol Toxicol

Role of inflammation in the mechanism of acetaminophen-induced hepatotoxicity

Expert Opin Drug Metab Toxicol

Basic—Liver, Pancreas, and Biliary Tract
Deletion of Apoptosis Signal-Regulating Kinase 1 Attenuates Acetaminophen-Induced Liver Injury by Inhibiting c-Jun N-Terminal Kinase Activation