Liver-Specific β-Catenin Knockout Mice Have Bile Canalicular Abnormalities, Bile Secretory Defect, and Intrahepatic Cholestasis
Open accessAbstract
Beta-catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of β-catenin in diet-induced steatohepatitis, we recently found that liver-specific β-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of β-catenin in biliary physiology. KO mice and wild-type (WT) littermates were fed standard chow or a diet supplemented with 0.5% cholic acid for 2 weeks. Chow-fed KO mice had higher serum and hepatic total bile acid levels and lower bile flow rate than WT mice. Expression levels of bile acid biosynthetic genes were lower and levels of major bile acid exporters were similar, which therefore could not explain the KO phenotype. Despite loss of the tight junction protein claudin-2, KO mice had preserved functional integrity of tight junctions. KO mice had bile canalicular morphologic abnormalities as evidenced by staining for F-actin and zona occludens 1. Electron microscopy revealed dilated and tortuous bile canaliculi in KO livers along with decreased canalicular and sinusoidal microvilli. KO mice on a cholic acid diet had higher hepatic and serum bile acid levels, bile ductular reaction, increased pericellular fibrosis, and dilated, misshapen bile canaliculi. Compensatory changes in expression levels of several bile acid transporters and regulatory genes were found in KO livers. Conclusion: Liver-specific loss of β-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for β-catenin in biliary physiology. (Hepatology 2010)
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β-catenin has roles in hepatic bile acid metabolism as well as mitochondrial function and energy balance, which have been linked to increased steatosis and liver injury in mice with hepatocellular deletion of β-catenin signalling components and in non-hepatic tissues.
“These findings match the role of β-catenin in hepatic bile acid metabolism35,39,45 as well as mitochondrial function and energy balance37,38, which have been linked to increased steatosis and liver injury in mice with hepatocellular deletion of β-catenin signalling components35,37–39 and in non-hepatic tissues46,47.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [45]
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Bile canalicular changes and defective bile secretion in Opisthorchis viverrini-infected hamsters
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Neuroprotective Compounds Isolated from Lysimachia christinae
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- Authors
- Yeh, T.-H., Krauland, L., Singh, V., Zou, B., Devaraj, P., Stolz, D. B., Franks, J., Monga, S. P. S., Sasatomi, E., & Behari, J.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Behari, Jaideep
- ORCID
- Venue
- Hepatology
- Published
- 2010-10
- Volume
- 52
- Issue
- 4
- Pages
- 1410-1419
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2947599
- OpenAlex
- W2010818022
- Cited by
- 81
- References
- 31
- Citations by year
- 2025: 4 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 8 · 2019: 9 · 2018: 8 · 2017: 12 · 2016: 4 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (K08AA017622)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- β-catenin, liver-specific knockout mice, intrahepatic cholestasis, bile secretion, bile acid transporters, bile acid synthesis, claudin-2, tight junctions, bile canaliculi, pericellular fibrosis, biliary tract physiology
- MeSH terms
- Animals, Bile, Bile Acids and Salts, Bile Canaliculi, Cholestasis, Intrahepatic, Diet, Female, Liver, Mice, Inbred C57BL, Mice, Knockout, Cholic Acid, beta Catenin, Mice
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