| First Author | Apte U | Year | 2009 |
| Journal | Am J Pathol | Volume | 175 |
| Issue | 3 | Pages | 1056-65 |
| PubMed ID | 19679878 | Mgi Jnum | J:152895 |
| Mgi Id | MGI:4360400 | Doi | 10.2353/ajpath.2009.080976 |
| Citation | Apte U, et al. (2009) Beta-catenin activation promotes liver regeneration after acetaminophen-induced injury. Am J Pathol 175(3):1056-65 |
| abstractText | 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. |
