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Am J Pathol. 2009 Sep;175(3):1056-65. doi: 10.2353/ajpath.2009.080976. Epub 2009 Aug 13.

Beta-catenin activation promotes liver regeneration after acetaminophen-induced injury.

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1
Division of Experimental Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street S-421 BST, Pittsburgh, PA 15261, USA.

Abstract

Acute liver failure (ALF) remains a disease with poor patient outcome. Improved prognosis is associated with spontaneous liver regeneration, which supports the relevance of exploring 'regenerative' therapies. Therefore, the role of the Wnt/beta-catenin pathway in liver regeneration following ALF was investigated. ALF was induced in mice by acetaminophen overdose, which is also a leading cause of liver failure in patients. beta-catenin distribution was also studied in liver sections from acetaminophen-induced ALF patients. A nonlethal dose of acetaminophen, which induces liver regeneration, led to stabilization and activation of beta-catenin for 1 to 12 hours. These data were also verified by increased expression of the beta-catenin surrogate target glutamine synthetase. Beta-catenin activation occurred secondary to the inactivation of glycogen synthase kinase-3beta and an increase in levels of casein kinase 2alpha, and led to increased cyclin-D1, another known beta-catenin target. These observations were next substantiated in beta-catenin conditional-null mice (beta-catenin-null), which show dampened regeneration after acetaminophen injury following induction of CYP2e1/1a2 expression. In light of decreased acetaminophen injury in beta-catenin-null mice despite CYP induction, equitoxic studies in control mice were performed. Significant differences in regeneration persisted following comparable injury in beta-catenin-null and control animals. Retrospective analysis of liver samples from acetaminophen-overdose patients demonstrated a positive correlation between nuclear beta-catenin, proliferation, and spontaneous liver regeneration. Thus, our studies demonstrate early activation of beta-catenin signaling during acetaminophen-induced injury, which contributes to hepatic regeneration.

PMID:
19679878
PMCID:
PMC2731124
DOI:
10.2353/ajpath.2009.080976
[Indexed for MEDLINE]
Free PMC Article
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