Mascarenhas, M.S.D.; (2007) Role of Hfe and hepcidin in the homeostasis of body iron levels. Doctoral thesis , University of London.

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Abstract

Recent studies have suggested that hepatic iron stores and the response to anaemia and inflammation are dependent on the mouse strains used and their Hfe status. Hepcidin and iron transporters such as DMT1 and Iregl are regulator molecules important in the pathology and physiology of Iron metabolism. The aim of these studies was to produce Hfe KO mice on a strain known to have higher basal hepatic iron levels and study iron homeostasis in relation to variable dietary iron and inflammation in these mice. The regulation of hepcidin was investigated in Huh7 cells exposed to various stimuli such as iron, inflammation and hypoxia. In addition, Huh7 cells were exposed to conditioned medium obtained from HH1 patient's macrophages. Results obtained from these studies are described and discussed in this thesis. In brief, it was found that the disruption of the Hfe gene causes a preferential accumulation of iron in the caudate lobe of the mouse liver. Contrary to previous findings, iron loaded diet does not have an effect on hepcidin expression in wt SWR mice while in Hfe KO SWR mice it significantly upregulates hepcidin expression. Furthermore, the upregulation of hepcidin by turpentine oil-induced inflammation in SWR mice is Hfe-dependent. Hepcidin expression is down regulated by hypoxia and anaemia and conditioned medium from patients with HH1 macrophages have no effect on hepcidin expression levels. In conclusion, the results show that SWR Hfe KO mice is not an accurate model for the study of HH1, the studies described here, however, contribute to the understanding of how hepatocytes respond to iron status, hypoxia and inflammation and the relevance of the Hfe gene in the regulation of hepcidin expression levels as well as hepatic DMT1 and Iregl expression levels.

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