title: Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model.
abstract: Acetaminophen (APAP) overdose results in acute liver failure and has limited treatment options. Previous studies show that stimulating liver regeneration is critical for survival after APAP overdose, but the mechanisms remain unclear. In this study, we identified major signaling pathways involved in liver regeneration after APAP-induced acute liver injury using a novel incremental dose model. Liver injury and regeneration were studied in C57BL/6 mice treated with either 300 mg/kg (APAP300) or 600 mg/kg (APAP600) APAP. Mice treated with APAP300 developed extensive liver injury and robust liver regeneration. In contrast, APAP600-treated mice exhibited significant liver injury but substantial inhibition of liver regeneration, resulting in sustained injury and decreased survival. The inhibition of liver regeneration in the APAP600 group was associated with cell cycle arrest and decreased cyclin D1 expression. Several known regenerative pathways, including the IL-6/STAT-3 and epidermal growth factor receptor/c-Met/mitogen-activated protein kinase pathways, were activated, even at APAP600, where regeneration was inhibited. However, canonical Wnt/β-catenin and NF-κB pathways were activated only in APAP300-treated mice, where liver regeneration was stimulated. Furthermore, overexpression of a stable form of β-catenin, where serine 45 is mutated to aspartic acid, in mice resulted in improved liver regeneration after APAP overdose. Taken together, our incremental dose model has identified a differential role of several signaling pathways in liver regeneration after APAP overdose and highlighted canonical Wnt signaling as a potential target for regenerative therapies for APAP-induced acute liver failure.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Bharat
authors.initials: B
authors.lastname: Bhushan
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Chad
authors.initials: C
authors.lastname: Walesky
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Michael
authors.initials: M
authors.lastname: Manley
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Tara
authors.initials: T
authors.lastname: Gallagher
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Prachi
authors.initials: P
authors.lastname: Borude
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Genea
authors.initials: G
authors.lastname: Edwards
authors.affiliation: Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas. Electronic address: uapte@kumc.edu.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000082:Acetaminophen