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Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors.
- Source :
-
Hepatology (Baltimore, Md.) [Hepatology] 2008 Dec; Vol. 48 (6), pp. 1998-2006. - Publication Year :
- 2008
-
Abstract
- Unlabelled: 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.<br />Conclusion: 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.
- Subjects :
- Animals
Anti-Inflammatory Agents pharmacology
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Cells, Cultured
Dexamethasone pharmacology
Glucose-6-Phosphatase metabolism
Hepatocytes cytology
Hepatocytes drug effects
Homeostasis physiology
Humans
Insulin pharmacology
Liver cytology
Liver drug effects
Liver Neoplasms metabolism
Liver Neoplasms pathology
Male
Nerve Tissue Proteins
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
RNA, Messenger metabolism
Rats
Rats, Wistar
Selenium metabolism
Signal Transduction physiology
Forkhead Transcription Factors metabolism
Hepatocyte Nuclear Factor 4 metabolism
Hepatocytes metabolism
Liver metabolism
RNA-Binding Proteins metabolism
Selenoprotein P metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1527-3350
- Volume :
- 48
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Hepatology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 18972406
- Full Text :
- https://doi.org/10.1002/hep.22526