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

• Published in: The American journal of pathology Vol. 175; no. 3; pp. 1056 - 1065
• Main Authors: Apte, Udayan, Singh, Sucha, Zeng, Gang, Cieply, Benjamin, Virji, Mohamed A, Wu, Tong, Monga, Satdarshan P.S
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.09.2009; ASIP; American Society for Investigative Pathology
• Subjects: Acetaminophen - adverse effects; Adult; Analgesics, Non-Narcotic - adverse effects; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Cell Proliferation; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2E1 - metabolism; Female; Gene Expression Regulation; Humans; Investigative techniques, diagnostic techniques (general aspects); Liver - metabolism; Liver - pathology; Liver Failure - chemically induced; Liver Failure - metabolism; Liver Failure - physiopathology; Liver Regeneration - physiology; Male; Medical sciences; Mice; Middle Aged; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Signal Transduction; Young Adult; Digestive system; Liver; Activation; Chenopodiaceae; Beta; Regeneration; Anatomic pathology; Paracetamol; Dicotyledones; Angiospermae; Spermatophyta; Lesion; Catenin
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080976

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 2α, 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.