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Cited by 59Alcohol Consumption and Health EffectsLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

β-Catenin is essential for ethanol metabolism and protection against alcohol-mediated liver steatosis in mice

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Liu, Shiguang, Yeh, Tzu-Hsuan, Singh, Vijay P., Shiva, Sruti, Krauland, Lindsay, Li, Huanan, Zhang, Pili, Kharbanda, Kusum +5 more·2012·Hepatology
DOI 10.1002/hep.24766PMC PMC3288318
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Abstract

The liver plays a central role in ethanol metabolism, and oxidative stress is implicated in alcohol-mediated liver injury. β-Catenin regulates hepatic metabolic zonation and adaptive response to oxidative stress. We hypothesized that β-catenin regulates the hepatic response to ethanol ingestion. Female liver-specific β-catenin knockout (KO) mice and wild-type (WT) littermates were fed the Lieber-Decarli liquid diet (5% ethanol) in a pairwise fashion. Liver histology, biochemistry, and gene-expression studies were performed. Plasma alcohol and ammonia levels were measured using standard assays. Ethanol-fed (EtOH) KO mice exhibited systemic toxicity and early mortality. KO mice exhibited severe macrovesicular steatosis and 5 to 6-fold higher serum alanine aminotransferase and aspartate aminotransferase levels. KO mice had a modest increase in hepatic oxidative stress, lower expression of mitochondrial superoxide dismutase (SOD2), and lower citrate synthase activity, the first step in the tricarboxylic acid cycle. N -Acetylcysteine did not prevent ethanol-induced mortality in KO mice. In WT livers, β-catenin was found to coprecipitate with forkhead box O3, the upstream regulator of SOD2. Hepatic alcohol dehydrogenase and aldehyde dehydrogenase activities and expression were lower in KO mice. Hepatic cytochrome P450 2E1 protein levels were up-regulated in EtOH WT mice, but were nearly undetectable in KO mice. These changes in ethanol-metabolizing enzymes were associated with 30-fold higher blood alcohol levels in KO mice. Conclusion : β-Catenin is essential for hepatic ethanol metabolism and plays a protective role in alcohol-mediated liver steatosis. Our results strongly suggest that integration of these functions by β-catenin is critical for adaptation to ethanol ingestion in vivo .

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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 [36]

    The Results report lower liver weight in β-catenin-knockout mice and altered lobular localization of alcohol-metabolizing enzymes; the Discussion describes β-catenin as a key player in hepatic metabolic zonation (page numbers unavailable). These passages support a role for β-catenin in liver size and function, but the paper does not establish HSC-derived RSPO3, hepatocyte LGR4, or HSC–hepatocyte cross-talk as the mechanism. (LLM, conf=0.86)

    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 [36]

    The Results report lower liver weight, defective ethanol metabolism, and greater steatosis and liver injury in β-catenin knockout mice; the Discussion also describes altered metabolic zonation. The paper does not report a regeneration result for these mice. The sentence’s RSPO3 interpretation is the citing authors’ framing, not a finding attributed to this source. (LLM, conf=0.86)

    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 [36]

  • 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 [36]

  • 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 [36]

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Authors
Liu, S., Yeh, T.-H., Singh, V. P., Shiva, S., Krauland, L., Li, H., Zhang, P., Kharbanda, K., Ritov, V., Monga, S. P. S., Scott, D. K., Eagon, P. K., & Behari, J.
Affiliations
  • University of Pittsburgh (US)
  • University of Nebraska at Omaha (US)
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2012-03
Volume
55
Issue
3
Pages
931-940
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.24766
PMC
PMC3288318
OpenAlex
W2019974905
Cited by
59
References
1
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 1 · 2015: 6 · 2014: 5 · 2013: 7 · 2012: 3
FWCI
3.37
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1279 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (K08AA017622)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R56DK065149)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
β-catenin, alcohol metabolism, oxidative stress, liver-specific knockout mice, manganese superoxide dismutase, alcohol dehydrogenase, aldehyde dehydrogenase, CYP2E1, liver injury, blood alcohol concentration
MeSH terms
Superoxide Dismutase 2, Alanine Transaminase, Ethanol, Ammonia, Animals, Aspartate Aminotransferases, Disease Models, Animal, Fatty Liver, Female, Liver, Mitochondria, Liver, Superoxide Dismutase, Mice, Knockout, Oxidative Stress, beta Catenin, Mice

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