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Cited by 102Mitochondrial Function and PathologyWnt/β-catenin signaling in development and cancerLiver physiology and pathology

β-Catenin Regulates Hepatic Mitochondrial Function and Energy Balance in Mice

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Lehwald, Nadja, Tao, Guo–Zhong, Jang, Kyu Yun, Papandreou, Ioanna, Liu, Bowen, Liu, Bo, Pysz, Marybeth A., Willmann, Jürgen K. +3 more·2012·Gastroenterology
DOI 10.1053/j.gastro.2012.05.048PMC PMC12045480
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Abstract

Background & aims Wnt signaling regulates hepatic function and nutrient homeostasis. However, little is known about the roles of β-catenin in cellular respiration or mitochondria of hepatocytes. Methods We investigated β-catenin's role in the metabolic function of hepatocytes under homeostatic conditions and in response to metabolic stress using mice with hepatocyte-specific deletion of β-catenin and their wild-type littermates, given either saline (sham) or ethanol (as a model of binge drinking and acute ethanol intoxication). Results Under homeostatic conditions, β-catenin-deficient hepatocytes demonstrated mitochondrial dysfunctions that included impairments to the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) and decreased production of adenosine triphosphate (ATP). There was no evidence for redox imbalance or oxidative cellular injury in the absence of metabolic stress. In mice with β-catenin-deficient hepatocytes, ethanol intoxication led to significant redox imbalance in the hepatocytes and further deterioration in mitochondrial function that included reduced OXPHOS, fatty acid oxidation (FAO), and ATP production. Ethanol feeding significantly increased liver steatosis and oxidative damage, compared with wild-type mice, and disrupted the ratio of nicotinamide adenine dinucleotide. β-catenin-deficient hepatocytes also had showed disrupted signaling of Sirt1/peroxisome proliferator-activated receptor-α signaling. Conclusions β-catenin has an important role in the maintenance of mitochondrial homeostasis, regulating ATP production via the tricarboxylic acid cycle, OXPHOS, and fatty acid oxidation; β-catenin function in these systems is compromised under conditions of nutrient oxidative stress. Reagents that alter Wnt-β-catenin signaling might be developed as a useful new therapeutic strategy for treatment of liver disease.

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  • 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 [37]

    The Results (page not provided) show that hepatocyte-specific β-catenin deletion impairs mitochondrial function and energy production; the Discussion also notes a reduced liver-to-body-weight ratio in β-catenin-deficient mice. These findings support a role for β-catenin in liver size and function, but the paper does not establish RSPO3–LGR4 signaling, HSC–hepatocyte cross-talk, or the proposed control of zonation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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 [37]

    The Results (page unavailable) show that β-catenin-deficient mice had greater hepatocellular injury after acute ethanol intoxication. The Discussion (page unavailable) also reports increased steatohepatitis after β-catenin deletion in an MCD-diet model. These passages support a role for β-catenin in hepatocyte injury, but not the claimed opposing functions across acute toxic and chronic metabolic injury; they do not address RSPO3. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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 [37]

    The Results report that hepatocyte-specific β-catenin deletion reduces hepatic ATP and increases injury after acute ethanol exposure; the Discussion also describes a reduced liver-to-body-weight ratio and delayed proliferation after partial hepatectomy. These findings support much of the comparison with β-catenin deletion, but our copy does not establish a matching effect on liver zonation. The sentence presents HSC-derived RSPO3 as the citing authors’ finding, not as a result of this source. (LLM, conf=0.85)

    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 [37]

  • 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 [37]

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Authors
Lehwald, N., Tao, G., Jang, K. Y., Papandreou, I., Liu, B., Liu, B., Pysz, M. A., Willmann, J. K., Knoefel, W. T., Denko, N. C., & Sylvester, K. G.
Affiliations
  • Stanford Medicine (US)
  • Jeonbuk National University Hospital (KR)
  • Heinrich Heine University Düsseldorf (DE)
  • Lucile Packard Children's Hospital (US)
Corresponding author
Sylvester, Karl G.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2012-09
Volume
143
Issue
3
Pages
754-764
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2012.05.048
PMC
PMC12045480
OpenAlex
W2067240474
Cited by
102
References
5
Citations by year
2026: 8 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 4 · 2019: 3 · 2018: 11 · 2017: 11 · 2016: 3 · 2015: 12 · 2014: 7 · 2013: 5
FWCI
3.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Children's Surgical Research Program Fund
  • Transplantation and Tissue Engineering Center
  • Packard Foundation for Children's Health
  • National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (DK56339)
  • YAEL Foundation and the German Research Foundation (DFG NL 2509/2-1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • 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, Wnt signaling, hepatocytes, mitochondrial function, oxidative phosphorylation, TCA cycle, fatty acid oxidation, ATP production, ethanol intoxication, binge drinking, hepatic steatosis, oxidative stress, NAD+/NADH ratio, hepatocyte-specific knockout mice
MeSH terms
Adenosine Triphosphate, Ethanol, Animals, Citric Acid Cycle, Disease Models, Animal, Energy Metabolism, Fatty Acids, Fatty Liver, Alcoholic, Homeostasis, Mice, Inbred C57BL, Mitochondria, Liver, Oxidation-Reduction, Oxidative Phosphorylation, Time Factors, Lipid Peroxidation, Mice, Knockout, Oxidative Stress, Hepatocytes, beta Catenin, Mice, Membrane Potential, Mitochondrial, Wnt Signaling Pathway

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