title: Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors.
abstract: Selenoprotein P (SeP), the major selenoprotein in plasma, is produced mainly by the liver, although SeP expression is detected in many organs. Recently, we reported stimulation of SeP promoter activity by the forkhead box transcription factor FoxO1a in hepatoma cells and its attenuation by insulin. Here, we demonstrate that this translates into fine-tuning of SeP production and secretion by insulin. Overexpression of peroxisomal proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha) enhanced the stimulatory effect of FoxO1a on SeP promoter activity. We identified a novel functional binding site for hepatocyte nuclear factor (HNF)-4alpha, termed hepatocyte nuclear factor binding element 1, in the human SeP promoter directly upstream of the FoxO-responsive element daf16-binding element 2 (DBE2). Point mutations in hepatocyte nuclear factor binding element 1 alone or together with DBE2 decreased basal activity and responsiveness of the SeP promoter to PGC-1alpha. Moreover, the PGC-1alpha-inducing glucocorticoid dexamethasone strongly enhanced SeP messenger RNA levels and protein secretion in cultured rat hepatocytes, whereas insulin suppressed the stimulation of both PGC-1alpha and SeP caused by dexamethasone treatment. In a brain-derived neuroblastoma cell line with low basal SeP expression, SeP transcription was stimulated by PGC-1alpha together with FoxO1a, and overexpression of HNF-4alpha potentiated this effect.
  
  
  CONCLUSIONS
  High-level expression of SeP in liver is ensured by concerted action of the coactivator PGC-1alpha and the transcription factors FoxO1a and HNF-4alpha. Hence, the production of SeP is regulated similarly to that of the gluconeogenic enzyme glucose-6-phosphatase. As hepatic SeP production is crucial for selenium distribution throughout the body, the present study establishes PGC-1alpha as a key regulator of selenium homeostasis.
authors.affiliation: Institute for Biochemistry and Molecular Biology I, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Speckmann
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Walter
authors.forename: Lirija
authors.initials: L
authors.lastname: Alili
authors.forename: Roland
authors.initials: R
authors.lastname: Reinehr
authors.forename: Helmut
authors.initials: H
authors.lastname: Sies
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Klotz
authors.forename: Holger
authors.initials: H
authors.lastname: Steinbrenner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012643:Selenium / Q000378:metabolism; D051149:Selenoprotein P / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D051858:Forkhead Transcription Factors; D005952:Glucose-6-Phosphatase; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012643:Selenium; D051149:Selenoprotein P; D014157:Transcription Factors; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1