Regulation of glutathione peroxidase-1 expression

Abstract

Studies on selenoprotein expression are revealing a hierarchy of selenoproteins with regard to the extent of regulation by dietary selenium status, and with regard to the dietary selenium requirement for maximal expression. In rats, liver glutathione peroxidase-1 (GPxl), liver type 1 deiodinase, and plasma selenoprotein P have the highest dietary selenium requirements to maintain plateau levels of selenoprotein. Liver GPxl, liver GPx4 and liver thioredoxin reductase-1 have the highest selenium requirements to maintain plateau levels of the mRNA. The 10-fold change in GPxl mRNA with changes in selenium status is the largest extent of regulation for any known selenoprotein. Regulation of selenoprotein translation by selenium, mediated by Sec-tRNA availability, also regulates the level of all selenoproteins. The unique and specific regulation of GPxl expression by selenium is mediated by GPxl mRNA stability, and involves nonsense-mediated mRNA decay. This regulation requires a functional SECIS element and a UGA codon, and the UGA must be followed by an intron. Our recent results indicate that GPxl mRNA in selenium-deficient rat liver is moderately abundant, and that GPxl mRNA increases more than 20-fold with selenium supplementation. We hypothesize that selenium regulation of GPxl expression is a major component of GPxl function in higher animals, and that in this role, GPxl serves as a biological selenium buffer that maintains modest selenium stores for future selenoprotein synthesis. This role of GPxl and the dramatic regulation of GPxl mRNA level by selenium status make GPxl mRNA an excellent molecular biology marker for assessment of selenium requirements.