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Cited by 6Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathologyDrug Transport and Resistance Mechanisms

Loss of β-catenin reveals a role for glutathione in regulating oxidative stress during cholestatic liver disease

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Balogun, Oluwashanu, Shao, Daniel, Carson, Matthew, King, Thalia, Kosar, Karis, Zhang, Rong, Zeng, Gang, Cornuet, Pamela +7 more·2024·Hepatology Communications
DOI 10.1097/hc9.0000000000000485PMC PMC11227358
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Abstract

Background: Cholestasis is an intractable liver disorder that results from impaired bile flow. We have previously shown that the Wnt/β-catenin signaling pathway regulates the progression of cholestatic liver disease through multiple mechanisms, including bile acid metabolism and hepatocyte proliferation. To further explore the impact of these functions during intrahepatic cholestasis, we exposed mice to a xenobiotic that causes selective biliary injury. Methods: α-naphthylisothiocyanate (ANIT) was administered to liver-specific knockout (KO) of β-catenin and wild-type mice in the diet. Mice were killed at 6 or 14 days to assess the severity of cholestatic liver disease, measure the expression of target genes, and perform biochemical analyses. Results: We found that the presence of β-catenin was protective against ANIT, as KO mice had a significantly lower survival rate than wild-type mice. Although serum markers of liver damage and total bile acid levels were similar between KO and wild-type mice, the KO had minor histological abnormalities, such as sinusoidal dilatation, concentric fibrosis around ducts, and decreased inflammation. Notably, both total glutathione levels and expression of glutathione-S-transferases, which catalyze the conjugation of ANIT to glutathione, were significantly decreased in KO after ANIT. Nuclear factor erythroid-derived 2-like 2, a master regulator of the antioxidant response, was activated in KO after ANIT as well as in a subset of patients with primary sclerosing cholangitis lacking activated β-catenin. Despite the activation of nuclear factor erythroid-derived 2-like 2, KO livers had increased lipid peroxidation and cell death, which likely contributed to mortality. Conclusions: Loss of β-catenin leads to increased cellular injury and cell death during cholestasis through failure to neutralize oxidative stress, which may contribute to the pathology of this disease.

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  • GSTMs are glutathione S-transferase family members within the mu subfamily that are activated upon WNT and NRF2 signaling.

    “GSTMs are glutathione S-transferase family members within the mu subfamily that are activated upon WNT and NRF2 signaling (40–43).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [43]

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Authors
Balogun, O., Shao, D., Carson, M., King, T., Kosar, K., Zhang, R., Zeng, G., Cornuet, P., Goel, C., Lee, E., Patel, G., Brooks, E., Monga, S. P., Liu, S., & Nejak-Bowen, K.
Affiliations
  • University of Pittsburgh (US)
  • Case Western Reserve University (US)
  • Duquesne University (US)
  • Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
ORCID
Venue
Hepatology Communications
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2024-07
Volume
8
Issue
7
ISSN
2471-254X (ISSN-L)
DOI
10.1097/hc9.0000000000000485
PMC
PMC11227358
OpenAlex
W4400353391
Cited by
6
References
1
Citations by year
2026: 2 · 2025: 4
FWCI
2.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology Communications (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124412, P30DK120531, R01DK103775)
  • National Institute of Biomedical Imaging and Bioengineering (T32EB001026)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
β-catenin, Wnt/β-catenin signaling, cholestatic liver disease, intrahepatic cholestasis, glutathione, oxidative stress, alpha-naphthylisothiocyanate, hepatocyte injury, glutathione S-transferase, Nrf2, lipid peroxidation, hepatocyte death, primary sclerosing cholangitis, biliary injury
MeSH terms
Animals, Bile Acids and Salts, Cholestasis, Intrahepatic, Disease Models, Animal, Female, Glutathione, Glutathione Transferase, Humans, Liver, Male, Mice, Inbred C57BL, 1-Naphthylisothiocyanate, Signal Transduction, Mice, Knockout, Oxidative Stress, Cell Proliferation, beta Catenin, NF-E2-Related Factor 2, Mice

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