Liver‐specific loss of β‐catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice†‡
Abstract
There is accumulating evidence that Wnt/beta-catenin signaling is involved in the regulation of liver development and physiology. The presence of genetic alterations resulting in constitutive beta-catenin stabilization in human and murine liver tumors also implicates this pathway in hepatocyte proliferation. In the present study, we generated hepatocyte-specific beta-catenin knockout mice to explore the role of beta-catenin in liver function. Conditional knockout mice were born at the expected Mendelian ratio and developed normally to adulthood, indicating beta-catenin is dispensable for essential liver function under normal breeding conditions. However, the liver mass of knockout mice was 20% less than those of mice in the control groups. Expression analysis revealed loss of genes required for glutamine synthesis in knockout mice. Loss of the liver glutamine synthesis pathway did not affect the blood ammonia level in mice fed a standard diet, yet, knockout mice showed significantly elevated blood ammonia levels with high-protein dietary feeding. Furthermore, the expression of two cytochrome P450 enzymes, CYP1A2 and CYP2E1, was almost completely abolished in livers from hepatocyte-specific beta-catenin knockout mice. Consequently, these mice were resistant to acetaminophen challenge, confirming the requirement of these cytochrome P450 enzymes for metabolism of xenobiotic substances. In conclusion, in addition to regulating hepatocyte proliferation, beta-catenin may also contr…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HSC-derived RSPO3, hepatocyte-expressed LGR4 and its downstream target β-catenin are central mediators of the HSC-hepatocyte cross-talk that controls liver size, zonation and function.
“Thus, Rspo3ΔHSC mice reproduced key aspects of HSC-depleted, Lgr4/Lgr5ΔHep and Ctnnb1ΔHep mice24,25,34–39, suggesting HSC-derived RSPO3, hepatocyte-expressed LGR4 and its downstream target β-catenin as central mediators of the HSC–hepatocyte cross-talk that controls liver size, zonation and function.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [34]
The β-catenin-WNT pathway promotes APAP- and CCl4-induced injury but protects from ALD, MASLD and ageing-induced injury.
“Together, these data align with the critical role of the β-catenin–WNT pathway in liver injury, promoting APAP- and CCl4-induced injury34 but protecting from ALD36,37, MASLD35,38,39 and ageing-induced injury43.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [34]
RSPO3 has seemingly opposing functions in acute toxic liver and chronic metabolic injury, aligning with the functions of its downstream target β-catenin in hepatocyte injury.
“The seemingly opposing functions of RSPO3 in acute toxic liver and chronic metabolic injury align with the functions of its downstream target β-catenin in hepatocyte injury34–39.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [34]
RSPO3-LGR4-mediated HSC-hepatocyte communication is a gatekeeper of liver function in health and disease.
“The critical impact of HSC-derived RSPO3 on liver size, zonation, metabolism, regeneration and injury matches findings in mice with hepatocyte-specific deletion of β-catenin or LGR4/524,25,34–39, rendering RSPO3–LGR4-mediated HSC–hepatocyte communication a gatekeeper of liver function in health and disease.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [34]
HSC-derived RSPO3 critically impacts liver size, zonation, metabolism, regeneration and injury.
“The critical impact of HSC-derived RSPO3 on liver size, zonation, metabolism, regeneration and injury matches findings in mice with hepatocyte-specific deletion of β-catenin or LGR4/524,25,34–39, rendering RSPO3–LGR4-mediated HSC–hepatocyte communication a gatekeeper of liver function in health and disease.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [34]
Ectopic Ctnnb1 activation by itself induces glutamine synthetase (Glul/GS) expression outside the endogenous GS expression normally observed in a two- to three-cell ring of hepatocytes around the central vein.
“In the liver, ectopic Ctnnb1 activation by itself induces glutamine synthetase (gene: Glul; protein: GS) expression outside of the endogenous GS expression normally observed in a two- to three-cell ring of hepatocytes around the central vein (CV) (28–32).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [32]
No citation lists for this paper
No citation lists for this paper yet — checked again daily.
References 42 · Cited by 295
- Authors
- Sekine, S., Lan, B. Y., Bedolli, M., Feng, S., & Hebrok, M.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Hebrok, Matthias
- Venue
- Hepatology
- Published
- 2006-04
- Volume
- 43
- Issue
- 4
- Pages
- 817-825
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2038927157
- Cited by
- 295
- References
- 42
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 16 · 2023: 19 · 2022: 18 · 2021: 17 · 2020: 14 · 2019: 14 · 2018: 11 · 2017: 18 · 2016: 13 · 2015: 11 · 2014: 12 · 2013: 14 · 2012: 5
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060533, P30DK026743)
- 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, Wnt/β-catenin signaling, hepatocyte-specific knockout, liver development, glutamine synthesis, blood ammonia, CYP1A2, CYP2E1, cytochrome P450, acetaminophen metabolism, xenobiotic metabolism, liver mass, hepatocyte proliferation
- MeSH terms
- Acetaminophen, Ammonia, Animals, Dietary Proteins, Drug Resistance, Gene Expression Regulation, Glutamine, Liver, Mice, Knockout, Hepatocytes, beta Catenin, Mice, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP2E1 Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
