Original Research
Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice

https://doi.org/10.1016/j.jcmgh.2020.09.002Get rights and content
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Background & Aims

Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and metabolic signals into complex cellular transcriptional programs, might act as a rheostat for APAP-toxicity.

Methods

Wildtype or conditional Ahr knockout mice lacking Ahr in hepatocytes (AlbΔ/ΔAhr) or myeloid cells (LysMΔ/ΔAhr) were treated with the specific Ahr ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) together with APAP.

Results

Ahr activation by ITE, which by itself was non-toxic, exacerbated APAP-induced hepatotoxicity compared to vehicle-treated controls, causing 80% vs. 0% mortality after administration of a normally sublethal APAP overdose. Of note, Ahr activation induced hepatocyte death even at APAP doses within the therapeutic range. Aggravated liver injury was associated with significant neutrophil infiltration; however, lack of Ahr in myeloid cells did not protect LysMΔ/ΔAhr mice from exacerbated APAP hepatotoxicity. In contrast, AlbΔ/ΔAhr mice were largely protected from ITE-induced aggravated liver damage, indicating that Ahr activation in hepatocytes, but not in myeloid cells, was instrumental for disease exacerbation. Mechanistically, Ahr activation fueled hepatic accumulation of toxic APAP metabolites by up-regulating expression of the APAP-metabolizing enzyme Cyp1a2, a direct Ahr downstream target.

Conclusions

Ahr activation in hepatocytes potentiates APAP-induced hepatotoxicity. Thus, individual exposition to environmental Ahr ligands might explain individual sensitivity to hyperacute liver failure.

Keywords

APAP
Acute Liver Failure
Ahr
Cyp1a2

Abbreviations used in this paper

Ahr
aryl hydrocarbon receptor
ALT
alanine aminotransferase
APAP
acetaminophen
AST
aspartate aminotransferase
GSH
glutathione
H&E
hematoxylin and eosin
HSC
hepatic stellate cell
NPC
nonparenchymal cell
TUNEL
terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling

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Conflicts of interest The authors disclose no conflicts.

Funding This study was supported by the Deutsche Forschungsgemeinschaft (CRC 841).