β‐Catenin and GSK‐3β are targets for regenerative therapies for acetaminophen‐induced acute liver failure (398.4)

• DOI: 10.1096/fasebj.28.1_supplement.398.4
• Publication Date: 2021-06-16T09:58:44Z
• Authors: Bharat Bhushan; Chad Walesky; Prachi Borude; Michael Manley; Udayan Apte
• Keywords: Liver Regeneration; Acetaminophen; Regenerative Medicine

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