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Originally published online as doi:10.2353/ajpath.2009.080976 on August 13, 2009

Published online before print August 13, 2009
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(American Journal of Pathology. 2009;175:1056-1065.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080976

Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced Injury

Udayan Apte*, Sucha Singh*, Gang Zeng*, Benjamin Cieply*, Mohamed A. Virji*, Tong Wu* and Satdarshan P.S. Monga*{dagger}

From the Departments of Pathology,* and Medicine,{dagger} University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

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/β-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. β-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 β-catenin for 1 to 12 hours. These data were also verified by increased expression of the β-catenin surrogate target glutamine synthetase. β-Catenin activation occurred secondary to the inactivation of glycogen synthase kinase-3β and an increase in levels of casein kinase 2{alpha}, and led to increased cyclin-D1, another known β-catenin target. These observations were next substantiated in β-catenin conditional-null mice (β-catenin-null), which show dampened regeneration after acetaminophen injury following induction of CYP2e1/1a2 expression. In light of decreased acetaminophen injury in β-catenin-null mice despite CYP induction, equitoxic studies in control mice were performed. Significant differences in regeneration persisted following comparable injury in β-catenin-null and control animals. Retrospective analysis of liver samples from acetaminophen-overdose patients demonstrated a positive correlation between nuclear β-catenin, proliferation, and spontaneous liver regeneration. Thus, our studies demonstrate early activation of β-catenin signaling during acetaminophen-induced injury, which contributes to hepatic regeneration.




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J. Behari, T.-H. Yeh, L. Krauland, W. Otruba, B. Cieply, B. Hauth, U. Apte, T. Wu, R. Evans, and S. P.S. Monga
Liver-Specific {beta}-Catenin Knockout Mice Exhibit Defective Bile Acid and Cholesterol Homeostasis and Increased Susceptibility to Diet-Induced Steatohepatitis
Am. J. Pathol., February 1, 2010; 176(2): 744 - 753.
[Abstract] [Full Text] [PDF]


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