Selenoprotein P (SeP) is the major selenoprotein in human plasma, acting as an antioxidant and serving the transport of selenium from the liver to extrahepatic tissues. We here demonstrate that the human SeP promoter responds to overexpression of FoxO1a as well as of a constitutively active form of FoxO1a. Two FoxO-responsive elements were identified and characterized by generation of point mutation and deletion constructs. Similarly, SeP mRNA was upregulated in response to activation of FoxO1a in rat hepatoma cells stably transfected with a hydroxytamoxifen-regulatable form of FoxO1a. Insulin, stimulating the phosphorylation and inactivation of FoxO1a via phosphomositide 3-kinase (PI3K) and Akt, suppressed SeP promoter activity and mRNA synthesis. This suppressive effect of insulin on SeP expression was attenuated by inhibitors of PI3K. In conclusion, the selenoprotein P promoter is a target of the Akt/ FoxO signal transduction cascade and SeP expression is regulated at the level of transcription by the forkhead box protein FoxO1a in human and rat hepatoma cells. (c) 2007 Elsevier Inc. All rights reserved.