Global Genomic Analysis Reveals Regeneration Associated Signaling Network After Acetaminophen Overdose

Abstract

Liver regeneration is critical determinant of survival following acetaminophen (APAP) overdose, but the mechanism of this regenerative response remain unclear. We developed an incremental dose model consisting of “regenerative” dose (300 mg/kg) and a “non‐regenerative” dose (600 mg/kg) of APAP in mice to study mechanisms of regeneration after APAP overdose. Here we compared microarray‐based IPA‐assisted global gene expression patterns after 300 or 600 mg/kg APAP treatment in mice. Analysis of unique genes revealed activation of cell cycle inducers specifically in APAP300 group while induction of cell cycle repressors specifically at APAP600. IPA analysis revealed that DNA replication and repair pathways were specifically altered only at APAP300. Upstream regulators analysis predicted that APAP300 treatment resulted in activation of Myc, FoxM1, HIF1α and β‐catenin target genes and inhibited HNF4α and TRIM24 regulated genes. Treatment of APAP600 dose resulted in activation of p53 and NFκB‐inhibitor A and inhibition of β‐catenin and C/EBPα target genes. Predicted role of β‐catenin and NFκB in regeneration is consistent with our confirmatory studies using ChIP and overexpression analysis in mice. In conclusion, our genome wide analysis identified dose dependent signaling interactions modulating liver regeneration after APAP overdose, which is useful tool to identifying novel therapeutic targets and building new computational models of liver regeneration.