Selenium deficiency constitutes a risk factor for the incidence and negative course of severe diseases including
sepsis,
stroke,
autoimmune diseases or
cancer. In this study,
hypoxia is identified as a powerful stimulus to redirect
selenoprotein biosynthesis causing reduced
selenoprotein P expression and diminished
selenium export from hepatocytes in favour of increased biosynthesis of the essential protective intracellular
phospholipid hydroperoxide glutathione peroxidase GPX4. Specifically,
hypoxia decreases transcript concentrations of central factors controlling
selenium and
selenocysteine metabolism including
selenophosphate synthetase-2, phosphoseryl-
tRNA(SerSec)
kinase and
selenocysteine lyase, which are all proven to be rate-limiting
enzymes in
selenoprotein biosynthesis. These effects are paralleled by a general decline of
selenoprotein expression; however, not all
selenoproteins are affected to the same extent by
hypoxia, and GPX4 constitutes an exception as its expression becomes slightly increased. Supplemental
selenium is able to overcome the
hypoxia-dependent down regulation of
selenoprotein expression in our cell culture model system, supporting the concept of using
selenium as an adjuvant treatment option in severe diseases. Although it remains to be tested whether these effects constitute a hepatocyte-specific response, the
selenium-dependent decline of
selenoprotein P biosynthesis under hypoxic conditions may explain the progressive
selenium deficit developing in severe diseases.