Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration.
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.
Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Bradley A
BA
Carlson
Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Ryuta
R
Tobe
Helmholtz Zentrum München, Institute for Developmental Genetics, Neuherberg, Germany.
Elena
E
Yefremova
Department of Biological Sciences, Towson University, Towson, MD, USA.
Petra A
PA
Tsuji
Office of the Director Diagnostic and Research Services Branch, National Institutes of Health, Bethesda, MD, USA.
Victoria J
VJ
Hoffmann
Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
Ulrich
U
Schweizer
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Vadim N
VN
Gladyshev
Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: hatfield@mail.nih.gov.
Dolph L
DL
Hatfield
Helmholtz Zentrum München, Institute for Developmental Genetics, Neuherberg, Germany. Electronic address: marcus.conrad@helmholtz-muenchen.de.
Marcus
M
Conrad
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009336:Necrosis / Q000235:genetics / Q000378:metabolism; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D014810:Vitamin E / Q000378:metabolism
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D014810:Vitamin E; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C000611332:glutathione peroxidase 4, mouse; D005978:Glutathione; D019803:Glutathione Disulfide
Ferroptosis; Lipid peroxidation; Selenoprotein