Dynamic and coordinated regulation of KEAP1-NRF2-ARE and p53/p21 signaling pathways is associated with acetaminophen injury responsive liver regeneration.

ABSTRACT

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury. Compensatory liver regeneration is crucial for the final outcome of toxicant-induced injury. However, the molecular mechanisms underlying compensatory liver regeneration in mice after APAP-induced liver injury are not completely understood. This study aimed to investigate the role of dynamic and coordinated regulation of Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2)- antioxidant response element (ARE) and p53/p21 pathways in APAP injury-responsive liver regeneration. We found that mice exhibited massive hepatic toxicity during the first 12 hours after 400 mg/kg APAP treatment, but responsive liver recovery occurred beyond 24 hours as demonstrated by histopathological and biochemical assessments. The expression and nuclear accumulation of NRF2 was increased after APAP treatment. The expression of NAD(P)H quinone oxidoreductase 1, glutamate-cysteine ligase modifier subunit, and heme oxygenase-1 was inhibited during the first 24 hours and then induced to limit oxidative damage. The content of p53 and its downstream target p21 were significantly increased upon APAP exposure and subsequently decreased to normal levels at 48 hours. Furthermore, levels of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration at 48 hours were enhanced, suggesting initiation of hepatocyte proliferation and tissue repair. These results demonstrated that dynamic and coordinated regulation of KEAP1-NRF2-ARE and p53/p21 signaling pathways was associated with compensatory liver regeneration after APAP-induced acute liver injury.