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Rapid activation of β‐catenin during liver regeneration following acetaminophen‐induced acute liver failure
Author(s) -
Apte Udayan M,
Micsenyi Amanda,
Muller Peggy,
Cieply Benjamin,
Monga Satdarshan P. S.
Publication year - 2006
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.20.5.a1379-c
Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF). Understanding the mechanisms of liver regeneration following APAP‐induced liver injury is thus 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. Investigation into the mechanisms of β‐catenin activation revealed involvement of canonical (GSK‐3β‐dependent) and non‐canonical (c‐met‐dependent) components. In addition, failure of β‐catenin activation was observed in mice treated with a lethal dose of APAP (700 mg/kg) along with suppression of liver regeneration. Primary hepatocytes isolated from β‐cat −/− mice exhibited pronounced susceptibility to nontoxic doses of APAP. Further, suppression of β‐catenin activation was observed in human APAP‐induced ALF liver samples. Taken together, these data demonstrate that activation of β‐catenin might be among the earliest events stimulating regeneration following APAP‐induced ALF. Thus β‐catenin activation might have therapeutic and prognostic implications in APAP hepatotoxicity (Supported by RSG‐03‐141‐01‐CNE and NIH ‐ 1RO1DK62277 to SPSM).