CHOP is a critical regulator of acetaminophen-induced hepatotoxicity

Dotan Uzi, Liran Barda, Viviana Scaiewicz, Maya Mills, Tobias Mueller, Agueda Gonzalez-Rodriguez, Angela M. Valverde, Takao Iwawaki, Yaacov Nahmias, Ramnik Xavier, Ray T. Chung, Boaz Tirosh, Oren Shibolet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims The liver is a major site of drug metabolism and elimination and as such is susceptible to drug toxicity. Drug induced liver injury is a leading cause of acute liver injury, of which acetaminophen (APAP) is the most frequent causative agent. APAP toxicity is initiated by its toxic metabolite NAPQI. However, downstream mechanisms underlying APAP induced cell death are still unclear. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have recently emerged as major regulators of metabolic homeostasis. UPR regulation of the transcription repressor CHOP promotes cell death. We analyzed the role of UPR and CHOP in mediating APAP hepatotoxicity. Methods A toxic dose of APAP was orally administered to wild type (wt) and CHOP knockout (KO) mice and damage mechanisms were assessed. Results CHOP KO mice were protected from APAP induced damage and exhibited decreased liver necrosis and increased survival. APAP metabolism in CHOP KO mice was undisturbed and glutathione was depleted at similar kinetics to wt. ER stress and UPR activation were overtly seen 12 h following APAP administration, a time that coincided with strong upregulation of CHOP. Remarkably, CHOP KO but not wt mice exhibited hepatocyte proliferation at sites of necrosis. In vitro, large T immortalized CHOP KO hepatocytes were protected from APAP toxicity in comparison to wt control cells. Conclusions CHOP upregulation during APAP induced liver injury compromises hepatocyte survival in various mechanisms, in part by curtailing the regeneration phase following liver damage. Thus, CHOP plays a pro-damage role in response to APAP intoxication.

Original languageEnglish
Pages (from-to)495-503
Number of pages9
JournalJournal of Hepatology
Volume59
Issue number3
DOIs
StatePublished - Sep 2013

Funding

FundersFunder number
Morasha Program of Israel Science Foundation1668/08
United States - Israel Binational Science Foundation2007083
Comunidad de MadridS2010/BMD-2423
Japan Society for the Promotion of Science24390049
Ministerio de Economía y Competitividad
Israel Science Foundation78/09
Instituto de Salud Carlos III
Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

    Keywords

    • Acetaminophen hepatotoxicity
    • Drug induced liver injury
    • Endoplasmic reticulum stress
    • Unfolded protein response

    Fingerprint

    Dive into the research topics of 'CHOP is a critical regulator of acetaminophen-induced hepatotoxicity'. Together they form a unique fingerprint.

    Cite this