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Article Dans Une Revue Biochemical Journal Année : 2011

GATA-4 transcription factor regulates hepatic hepcidin expression.

Résumé

Hepcidin, an hormone mainly synthesized by hepatocytes and secreted in plasma, controls iron bioavailability. Thus, by inducing the internalization of the iron exporter ferroportin, it regulates iron release from macrophages, enterocytes and hepatocytes towards plasma. Abnormal levels of hepcidin expression alter plasma iron parameters and lead to iron metabolism disorders. To understand the mechanisms controlling hepcidin gene expression is therefore an important goal. We identified a potential GATA binding site within the human hepcidin promoter. Indeed, in hepatic HepG2 cells, luciferase experiments demonstrated that mutation of this GATA binding site impaired the hepcidin promoter transcriptional activity in basal condition. Gel retardation experiment showed that GATA-4 could bind this site. Cotransfection of GATA-4 expression vector with an hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity. Furthermore, modulation of GATA-4 mRNA expression using specific siRNAs downregulated endogenous hepcidin gene expression. Finally, we found that mutation of the GATA binding site impaired the interleukin-6 induction of hepcidin gene expression, but did not prevent the bone morphogenetic protein-6 response. In conclusion, our findings: i) indicate that GATA-4 may participate to the control of hepcidin expression, and ii) suggest that alteration of its expression could contribute to the development of iron-related disorders.

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Dates et versions

hal-00608393 , version 1 (13-07-2011)

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Marie-Laure Island, Nadia Fatih, Patricia Leroyer, Pierre Brissot, Olivier Loréal. GATA-4 transcription factor regulates hepatic hepcidin expression.. Biochemical Journal, 2011, 437 (3), pp.477-482. ⟨10.1042/BJ20110225⟩. ⟨hal-00608393⟩
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