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β‐Catenin is essential for liver regeneration following acetaminophen‐induced acute liver failure.
Author(s) -
Apte Udayan,
Zeng Gang,
Cieply Benjamin,
Kaestner Klaus,
Monga Satdarshan P. S.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1136-a
Subject(s) - acetaminophen , liver regeneration , cyp2e1 , wnt signaling pathway , liver injury , regeneration (biology) , pharmacology , medicine , chemistry , signal transduction , biology , microbiology and biotechnology , biochemistry , metabolism , cytochrome p450
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.