Removal of Glutathione Peroxidase 4 in Mouse Liver Leads to Early Lethality and Vitamin E Can Compensate for Its Loss

Abstract

Glutathione peroxidase 4 (GPx4) is one of several glutathione peroxidases found in mammals and its targeted deletion is early embryonic lethal. The primary functions of GPx4 are to protect cells against membrane lipid peroxidation and to govern a novel form of non‐apoptotic cell death, called ferroptosis, which appears to be relevant in a select set of organs. To study the role of GPx4 in liver tissue, a conditional knockout of Gpx4 in hepatocytes was used, along with thioredoxin reductase 1 (TrxR1) and selenocysteine (Sec) tRNA (Trsp) hepatocyte knockout mice as controls. In contrast to TrxR1‐ and Trsp‐deficient mice, Gpx4 knockout mice died within 48 hours after birth and presented extensive hepatocyte degeneration. We further found that Gpx4 knockout pups born from mothers fed a vitamin E‐enriched diet did not experience early death, demonstrating that vitamin E rescued Gpx4 knockout‐induced cell death. When vitamin E was subsequently removed from the diet, Gpx4‐deficient mice had an average survival time of approximately four weeks. We also crossed Trsp‐deficient and Gpx4‐deficient mice and were unable to obtain combined Trsp/Gpx4‐deficient mice at birth, indicating that the combined deficiency resulted in embryonic death. Combined Trsp/TrxR1‐deficient mice were born but had significantly shorter lifespans than either single knockout, suggesting that TrxR1 plays an important role in longevity of mice lacking Trsp in hepatocytes. This study demonstrates that GPx4 is critical for hepatocyte survival and proper liver function, and that vitamin E can compensate for its loss by protecting cells against lipid peroxidation.Support or Funding InformationThis work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.