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Title

CHOP is a critical regulator of acetaminophen-induced hepatotoxicity

AuthorsGonzález-Rodríguez, Águeda; Valverde, Ángela M.; Shibolet, Oren
Issue Date2013
PublisherElsevier
CitationJournal of Hepatology 59(3): 495-503 (2013)
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.
Descriptionet al.
URIhttp://hdl.handle.net/10261/123844
DOI10.1016/j.jhep.2013.04.024
Identifiersdoi: 10.1016/j.jhep.2013.04.024
issn: 0168-8278
e-issn: 1600-0641
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