Premium
β‐Catenin and GSK‐3β are targets for regenerative therapies for acetaminophen‐induced acute liver failure (398.4)
Author(s) -
Bhushan Bharat,
Walesky Chad,
Borude Prachi,
Manley Michael,
Apte Udayan
Publication year - 2014
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.28.1_supplement.398.4
Subject(s) - wnt signaling pathway , liver regeneration , regeneration (biology) , acetaminophen , pharmacology , medicine , regenerative medicine , microbiology and biotechnology , signal transduction , biology , stem cell
Acetaminophen (APAP) overdose is the major cause of acute liver failure (ALF) with limited treatment options. Liver regeneration is a critical determinant of survival after APAP overdose and regenerative therapies hold a great potential to treat APAP‐induced ALF. However, mechanisms of regeneration following APAP overdose are not known. We did a comprehensive analysis of pathways involved in liver regeneration using a novel incremental dose model of a “regenerative” dose (300 mg/kg, APAP300) and a “non‐regenerative” dose (600 mg/kg, APAP600) of APAP in mice. Stimulation of regeneration at APAP300 resulted in complete recovery, while inhibited regeneration at APAP600 resulted in delayed recovery and decreased survival. The inhibition of regeneration in APAP600 was due to inhibited cyclinD1 expression leading to delayed cell cycle. Further biochemical and genomic analysis revealed that many known regenerative pathways (e.g. EGFR/c‐Met, STAT3, MAPKs) remain activated even at non‐regenerative dose. However, Wnt/β‐catenin was specifically activated only at the regenerative dose. ChIP analysis revealed increased binding of β‐catenin to cyclinD1 promoter only at APAP300 correlating with higher cyclinD1 induction and liver regeneration. Further, mice overexpressing stable form of β‐catenin exhibited significantly higher regeneration and faster recovery after APAP overdose. Finally, pharmacological inhibition of GSK3β, the upstream regulator of β‐catenin, as late as 4 hr after APAP600 dose resulted in cyclinD1 induction and improved regeneration. These data demonstrate that canonical Wnt signaling pathway is a target for regenerative therapies for APAP‐induced ALF. Grant Funding Source : NIH ‐ R01 DK098414, P20 RR021940‐07 and AASLD‐ALF Liver Scholar Award (Udayan Apte)