Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration
Open accessAbstract
The selenoenzyme glutathione peroxidase 4 (Gpx4) is an essential mammalian glutathione peroxidase, which protects cells against detrimental lipid peroxidation and governs a novel form of regulated necrotic cell death, called ferroptosis. To study the relevance of Gpx4 and of another vitally important selenoprotein, cytosolic thioredoxin reductase (Txnrd1), for liver function, mice with conditional deletion of Gpx4 in hepatocytes were studied, along with those lacking Txnrd1 and selenocysteine (Sec) tRNA ( Trsp ) in hepatocytes. Unlike Txnrd1 - and Trsp -deficient mice, Gpx4 −/− mice died shortly after birth and presented extensive hepatocyte degeneration. Similar to Txnrd1 -deficient livers, Gpx4 −/− livers manifested upregulation of nuclear factor (erythroid-derived)-like 2 (Nrf2) response genes. Remarkably, Gpx4 −/− pups born from mothers fed a vitamin E-enriched diet survived, yet this protection was reversible as subsequent vitamin E deprivation caused death of Gpx4 -deficient mice ~4 weeks thereafter. Abrogation of selenoprotein expression in Gpx4 −/− mice did not result in viable mice, indicating that the combined deficiency aggravated the loss of Gpx4 in liver. By contrast, combined Trsp / Txnrd1 -deficient mice were born, but had significantly shorter lifespans than either single knockout, suggesting that Txnrd1 plays an important role in supporting liver function of mice lacking Trsp . In sum our study demonstrates that the ferroptosis regulator Gpx4 is critical for hepatocyte survival and proper liver function, and that vitamin E can compensate for its loss by protecting cells against deleterious lipid peroxidation.
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Inducible or tissue-specific ablation of Gpx4 in mice provokes acute renal or hepatic injury, neurodegeneration, and defective immunity to infection, all preventable or mitigated by ferroptosis-inhibiting strategies.
“the inducible or tissue-specific ablation of Gpx4 in mice provokes a variety of pathological conditions, including acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [589]
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- Authors
- Carlson, B. A., Tobe, R., Yefremova, E., Tsuji, P. A., Hoffmann, V. J., Schweizer, U., Gladyshev, V. N., Hatfield, D. L., & Conrad, M.
- Affiliations
- National Institutes of Health (US)
- Helmholtz Munich (DE)
- Towson University (US)
- University of Bonn (DE)
- Brigham and Women's Hospital (US)
- Corresponding author
- Hatfield, Dolph L.
- Conrad, Marcus
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 9
- Pages
- 22-31
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC4900515
- OpenAlex
- W2408722709
- Cited by
- 316
- References
- 40
- Citations by year
- 2026: 27 · 2025: 38 · 2024: 52 · 2023: 40 · 2022: 47 · 2021: 27 · 2020: 22 · 2019: 16 · 2018: 24 · 2017: 14 · 2016: 8
- FWCI
- 21.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Site cant be reached (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Cancer Institute
- Center for Cancer Research
- Deutsche Forschungsgemeinschaft (CO 291/2-3, CO 291/5-1)
- Human Frontier Science Program (RGP0013/14)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- GPX4, vitamin E, ferroptosis, hepatocyte degeneration, selenoproteins, thioredoxin reductase 1, selenocysteine tRNA, lipid peroxidation, conditional knockout mice, liver function, hepatocyte viability
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Cell Survival, Female, Gene Expression Regulation, Genotype, Glutathione, Glutathione Peroxidase, Liver, Liver Regeneration, Male, Necrosis, Vitamin E, Lipid Peroxidation, Mice, Knockout, Glutathione Disulfide, Hepatocytes, NF-E2-Related Factor 2, Mice
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