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Recent Advances in Nutritional Sciences

New Roles for an Old Selenoenzyme: Evidence from Glutathione Peroxidase-1 Null and Overexpressing Mice^1,2

Department of Animal Science, Cornell University, Ithaca, NY 14853 and ^* Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

³To whom correspondence should be addressed. E-mail: XL20{at}cornell.edu.

Cellular glutathione peroxidase-1 (GPX1) is the first identified and the most abundant selenoprotein in mammals. Although GPX1 has been widely considered to be a major antioxidant enzyme, there has been no direct evidence for such role in vivo until GPX1 transgenic and null mice became available 10 y ago. Using these new models, we demonstrated that GPX1 protects against oxidative stress mediated by reactive oxygen species (ROS), and the physiologic importance of this protection varies with insult level and body Se status. Full expression of GPX1 is needed, and overexpression of GPX1 is beneficial for Se-adequate mice to defend against severe oxidative stress. This function of GPX1 is associated with attenuating the prooxidant-induced oxidation of NADPH, NADH, lipid, and protein in various tissues. In Se-deficient mice, a minute amount of GPX1 activity (4% of adequate levels) protects against hepatic aponecrosis induced by mild oxidative stress. In contrast, knockout of GPX1 renders mice and their hepatocytes resistant to oxidative stress related to reactive nitrogen species (RNS). More intriguingly, mice overexpressing GPX1 develop insulin resistance and obesity, accompanied by a downregulation of insulin-mediated phosphorylations of insulin receptor and Akt protein. In conclusion, GPX1 seems to play contrasting roles in coping with ROS vs. RNS, and its metabolic functions extend beyond redox regulation.

KEY WORDS: • glutathione peroxidase-1 • selenium • signaling • oxidative stress • insulin resistance

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