β-Catenin Links Hepatic Metabolic Zonation with Lipid Metabolism and Diet-Induced Obesity in Mice
Open accessAbstract
β-catenin regulates the establishment of hepatic metabolic zonation. To elucidate the functional significance of liver metabolic zonation in the chronically overfed state in vivo, we fed a high-fat diet (HFD) to hepatocyte-specific β-catenin transgenic (TG) and knockout (KO) mice. Chow-fed TG and KO mice had normal liver histologic findings and body weight. However, HFD-fed TG mice developed prominent perivenous steatosis with periportal sparing. In contrast, HFD-fed KO mice had increased lobular inflammation and hepatocyte apoptosis. HFD-fed TG mice rapidly developed diet-induced obesity and systemic insulin resistance, but KO mice were resistant to diet-induced obesity. However, β-catenin did not directly affect hepatic insulin signaling, suggesting that the metabolic effects of β-catenin occurred via a parallel pathway. Hepatic expression of key glycolytic and lipogenic genes was higher in HFD-fed TG and lower in KO mice compared with wild-type mice. KO mice also exhibited defective hepatic fatty acid oxidation and fasting ketogenesis. Hepatic levels of hypoxia inducible factor-1α, an oxygen-sensitive transcriptional regulator of glycolysis and a known β-catenin binding partner, were higher in HFD-fed TG and lower in KO mice. KO mice had attenuated perivenous hypoxia, suggesting disruption of the normal sinusoidal oxygen gradient, a major determinant of liver carbohydrate and liver metabolism. Canonical Wnt signaling in hepatocytes is essential for the development of diet-induced fatty liver and obesity.
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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 [38]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredHSC-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 [38]
The Abstract and Discussion (page not specified in our copy) show that hepatocyte β-catenin regulates hepatic metabolic zonation and functions in knockout mice. They do not establish HSC-derived RSPO3, hepatocyte LGR4, or an HSC–hepatocyte cross-talk pathway controlling liver size. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRSPO3-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 [38]
The Abstract and Discussion report that hepatocyte β-catenin deletion disrupts metabolic zonation and metabolic responses; the Discussion also reports increased hepatocyte apoptosis and inflammation under a high-fat diet. These findings support part of the cited comparison, but this paper does not establish RSPO3–LGR4-mediated HSC–hepatocyte communication or report a regeneration finding. The gatekeeper characterization is the citing authors’ conclusion, not a finding of this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRSPO3 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 [38]
The ‘β-Catenin Links Hepatic Lipid Metabolism’ results report that high-fat-diet-fed β-catenin knockout mice had increased hepatocyte apoptosis and inflammation, supporting the chronic metabolic-injury part of the comparison. The paper does not address RSPO3 or establish the claimed opposing role of β-catenin in acute toxic liver injury. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHSC-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 [38]
The Animals and Dietary Treatments section identifies liver-specific β-catenin knockout mice, and the Discussion reports effects on metabolic zonation, metabolism, and high-fat-diet-associated hepatocyte injury. The paper does not report regeneration in those knockout mice; its Results also say their livers had a similar gross appearance to controls on a high-fat diet. Thus, it supports only part of the claimed match across liver size, zonation, metabolism, regeneration, and injury. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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 [38]
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Cites
Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes
Grant, S. F. A., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Manolescu, A., Sainz, J., Helgason, A., Stefansson, H., Emilsson, V., Helgadottir, A., et al. (2006) · Nature Genetics · doi:10.1038/ng1732 · Cited by 2,287 · see citing works
Perrone, C. E., Mattocks, D. A. L., Jarvis-Morar, M., Plummer, J. D., & Orentreich, N. (2010) · Metabolism · doi:10.1016/j.metabol.2009.10.023 · Cited by 136 · see citing works
Yeh, T.-H., Krauland, L., Singh, V., Zou, B., Devaraj, P., Stolz, D. B., Franks, J., Monga, S. P. S., Sasatomi, E., & Behari, J. (2010) · Hepatology · doi:10.1002/hep.23801 · Cited by 81 · see citing works
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Hepatic stellate cells control liver zonation, size and functions via R-spondin 3
Sugimoto, A., Saito, Y., Wang, G., Sun, Q., Yin, C., Lee, K. H., Geng, Y., Rajbhandari, P., Hernandez, C., Steffani, M., et al. (2025) · Nature · doi:10.1038/s41586-025-08677-w · Cited by 110 · see citing works
Self-citationGajos-Michniewicz, A., & Czyz, M. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2023.02.050 · Cited by 89 · see citing works
Role and Regulation of Wnt/β-Catenin in Hepatic Perivenous Zonation and Physiological Homeostasis
Goel, C., Monga, S. P., & Nejak-Bowen, K. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.09.007 · Cited by 53 · see citing works
The RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease
Annunziato, S., Sun, T., & Tchorz, J. S. (2022) · Hepatology · doi:10.1002/hep.32328 · Cited by 45 · see citing works
- Authors
- Behari, J., Li, H., Liu, S., Stefanovic-Racic, M., Alonso, L., O'Donnell, C. P., Shiva, S., Singamsetty, S., Watanabe, Y., Singh, V. P., & Liu, Q.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Behari, Jaideep
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 184
- Issue
- 12
- Pages
- 3284-3298
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC4258504
- OpenAlex
- W2141664611
- Cited by
- 65
- References
- 3
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 2 · 2022: 7 · 2021: 5 · 2020: 9 · 2019: 9 · 2018: 3 · 2017: 9 · 2016: 4 · 2015: 1 · 2014: 1
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5K08AA017622)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- 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
- Keywords
- β-catenin, diet-induced obesity, high-fat diet, hepatocyte-specific knockout mice, insulin resistance, hepatic fatty acid oxidation, ketogenesis, hypoxia-inducible factor-1α, Wnt signaling, liver inflammation, hepatocyte apoptosis, glycolysis, lipogenesis
- MeSH terms
- Animals, Hypoxia, Body Weight, Fatty Acids, Fatty Liver, Glycolysis, Immunohistochemistry, Inflammation, Insulin, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Mitochondria, Obesity, Oxygen, Signal Transduction, Apoptosis, Mice, Knockout, Hepatocytes, Lipid Metabolism, beta Catenin, Mice, Diet, High-Fat
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