Abstract
Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF). Understanding the mechanisms of liver regeneration following APAP-induced liver injury are of high therapeutic relevance. To investigate the role of Wnt/β-catenin, an important pathway in liver biology, in liver regeneration after APAP-induced ALF, male CD-1 mice were treated with a non-lethal dose of APAP (500 mg/kg), which induced extensive liver injury and subsequent regeneration. Rapid induction in the total and active β-catenin was evident at 1–3 hr after APAP treatment, along with its nuclear translocation at 6 hr. Further studies revealed that both canonical (GSK-3β-dependent) and non-canonical (c-met-dependent) pathways were involved in β-catenin activation. Administration of a lethal dose of APAP (700 mg/kg) known to inhibit liver regeneration completely suppressed β-catenin activation. Further, β-catenin conditional knockout mice, which have low CYP2E1 expression, exhibited increased APAP-mediated injury and decreased cell proliferation following CYP2E1 induction. Furthermore, suppression of β-catenin activation was observed in human APAP-induced ALF liver samples along with suppression of liver regeneration. Taken together, these data indicate that β-catenin activation plays an important role in stimulation of liver regeneration following APAP overdose and might have therapeutic and prognostic implications in APAP ALF.
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