Beta-catenin activation promotes liver regeneration after acetaminophen-induced injury.
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.
Apte
Udayan
U
Division of Experimental Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street S-421 BST, Pittsburgh, PA 15261, USA.
Singh
Sucha
S
Zeng
Gang
G
Cieply
Benjamin
B
Virji
Mohamed A
MA
Wu
Tong
T
Monga
Satdarshan P S
SP
D000082:Acetaminophen / Q000009:adverse effects*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D049109:Cell Proliferation; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015398:Signal Transduction; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D051176:beta Catenin; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2
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