Gender-Specific Interplay of Signaling through β-Catenin and CAR in the Regulation of Xenobiotic-Induced Hepatocyte Proliferation
Abstract
Aberrant signaling through the Wnt/β-catenin pathway is a critical determinant in human and rodent liver carcinogenesis and generally accepted to be a potent driver of proliferation. Xenobiotic agonists of the constitutive androstane receptor (CAR) induce massive acute hyperplasia of mouse liver and facilitate the outgrowth of hepatocellular carcinomas with activated β-catenin. In the present study, the interplay of β-catenin-dependent and CAR-dependent signaling in the liver and its effect on hepatocyte proliferation were analyzed in transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding β-catenin) following treatment with two CAR agonists, 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) and phenobarbital. Hepatocyte-specific knockout of β-catenin inhibited CAR agonists-induced hepatocyte proliferation in male mice. By contrast, the proliferative effect of CAR agonists was strongly augmented in female β-catenin knockout animals. This was due to prolonged proliferation of the knockout hepatocytes. CAR-mediated hepatocyte proliferation was, at least in part, dependent on estrogen signaling and was associated with enhanced expression of FoxM1 and elevated activity of the PDK1/p90RSK pathway. In conclusion, our study shows that gender-specific factors determine whether β-catenin signaling plays a pro- or an antiproliferative role in the regulation of mouse hepatocyte proliferation induced by CAR agonists.
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CAR's pro-proliferative role in liver is mediated through induction of c-Myc, Foxm1, and cyclin D1, and modulation of β-catenin and YAP signaling pathways.
“Prior studies have focused primarily on the pro-proliferative role of CAR in the liver, mediated through the induction of factors such as cellular-myelocytomatosis oncogene (c-Myc),15 forkhead box m1 (Foxm1),15 and cyclin D1 (Ccnd1),16 as well as modulation of β-catenin17,18 and Yes-associated protein19, 20, 21, 22 signaling pathways.”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [17]
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Self-citation
- Authors
- Braeuning, A., Heubach, Y., Knorpp, T., Kowalik, M. A., Templin, M., Columbano, A., & Schwarz, M.
- Affiliations
- University of Tübingen (DE)
- Natural and Medical Sciences Institute (DE)
- University of Cagliari (IT)
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-06-24
- Volume
- 123
- Issue
- 1
- Pages
- 113-122
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2127625114
- Cited by
- 40
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 6 · 2013: 4 · 2012: 1
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- β-catenin signaling, Wnt/β-catenin signaling, constitutive androstane receptor, hepatocyte proliferation, hepatocarcinogenesis, sex differences, estrogen signaling, FOXM1, TCPOBOP, phenobarbital
- MeSH terms
- Forkhead Box Protein M1, Animals, Female, Gene Expression Regulation, Male, Phenobarbital, Pyridines, Sex Factors, Protein Serine-Threonine Kinases, Mice, Knockout, Hepatocytes, Ribosomal Protein S6 Kinases, 90-kDa, Protein Array Analysis, Cell Proliferation, beta Catenin, Mice, Recoverin, Forkhead Transcription Factors, Wnt Signaling Pathway, 3-Phosphoinositide-Dependent Protein Kinases
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