Salama, M.F.I.; (2010) Regulation of hepcidin and hemojuvelin expression and their role in iron homeostasis. Doctoral thesis , UCL (University College London).

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Abstract

Hepcidin is the key regulator of iron homeostasis acting as a negative regulator of intestinal iron absorption. Several proteins have recently been identified to act as upstream regulators of hepcidin expression, such as HFE and hemojuvelin (HJV). Although hepcidin is regulated by iron, the molecules involved in this regulation and whether HFE is involved in this regulation remain to be clarified. The aims of this study were to investigate the molecules involved in hepcidin regulation by iron and the role played by HFE in this regulation, to understand the regulation of hepcidin and HJV expression during inflammation, and finally to investigate the possible role of upstream stimulatory factors (USFs) in the regulation of HJV expression. Wild type and HFE KO animal models were used to investigate the regulation of hepcidin by iron in vivo; the same animal models and in vitro studies were conducted to study the regulation of hepcidin and HJV expression during inflammation. A possible regulation of HJV by USFs was also examined in vitro and in vivo using ChIP assay. In this study, it was found that iron regulates the expression of BMP-6, for which HJV acts as a co-receptor, and phosphorylation of SMADs 1/5/8 in the liver which in turn may regulate hepcidin gene expression in response to different iron status. Moreover, HFE seems to be involved in the regulation of downstream signalling of BMP-6 that regulates hepcidin expression in response to iron loading. It was also found that the pro-inflammatory cytokines regulate hepcidin and HJV expression differently during inflammation. TNF-alpha seems to act directly on HJV to suppress its transcription possibly via a TNFRE within the HJV promoter, while IL-6 induces hepcidin expression via STAT3 signalling. In addition, acute inflammation studies in mice showed that although hepcidin expression is upregulated as a result of inflammation, HJV and BMP expression is selectively repressed in the liver suggesting a crucial requirement for the downregulation of these genes in order to induce hepcidin during inflammation in vivo. However, this response seems to be HFE-independent. Finally, the study showed an interaction between USFs and the HJV promoter both in vitro and in vivo suggesting that USFs are important for the regulation of hemojuvelin expression, and further strengthen the link between these transcription factors and iron metabolism.

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