Author: Patarabutr MasaratanaPublisher:
ISBN:
Category : Iron
Languages : en
Pages : 660
Book Description
Hepcidin, the iron regulatory peptide, has been shown to inhibit iron absorption and reticuloendothelial iron recycling. Hereditary haemochromatosis is genetic iron overload disorders mostly caused by mutations of genes encoding hepcidin or iron sensing molecules. The studies in this thesis were conducted to further delineate the pathophysiology of iron loading and explore therapeutic options for such conditions. -- Hepcidin deficiency results in systemic iron overload as evidenced through the two mouse models used in the current study, hypotransferrinaemic (hpx/hpx) and hepcidinI knockout (HepcI-/-) mice. Hepcidin injection caused hypoferraemia in wild type mice, but not HepcI-/- mice. However, the treatment inhibited iron absorption, especially the uptake step, in the knockout. Hepcidin administration was also associated with decreased expression of the iron exporter, ferroportin, preferentially in the spleen. Despite a crucial role of hepcidin in iron loading, its application as therapeutic modality requires further investigation as differential response was found between normal and hepcidin-deficient mice. -- Another important contributor of haemochromatosis is tissue uptake of nontransferrin-bound iron (NTBI). A few NTBI transporters have been identified including L-type voltage dependent calcium channels (LVDCCs) and a zinc transporter, Zip14. The interference of these NTBI transporters to modulate iron loading was therefore explored. The administration of verapamil, a LVDCC blocker, was associated with a global reduction in tissue iron levels in hpx/hpx, but not HepcI-/- mice. This was achieved through a yet unclarified mechanism. In contrast, dietary supplementation of zinc in HepcI-/- mice resulted in reduced iron accumulation specifically in the liver.