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Biochemical, Molecular, and Genetic Mechanisms

Hepcidin Decreases Iron Transporter Expression in Vivo in Mouse Duodenum and Spleen and in Vitro in THP-1 Macrophages and Intestinal Caco-2 Cells^1–3,

⁴ Nutritional Sciences Division, King's College London, London SE1 9NH, UK; ⁵ Department of Neuroscience, Physiology and Pharmacology, University College London, London NW3 2PF, UK; and ⁶ Department of Structural and Molecular Biology, University College London, London WC1E 6BT, UK

Hepcidin is thought to control iron metabolism by interacting with the iron efflux transporter ferroportin. In macrophages, there is compelling evidence that hepcidin directly regulates ferroportin protein expression. However, the effects of hepcidin on intestinal ferroportin levels are less conclusive. In this study, we compared the effects of hepcidin on iron transporter expression in the spleen and duodenum of mice treated with hepcidin over a 24- to 72-h period and observed a marked decrease in the expression of ferroportin in both duodenal enterocytes and splenic macrophages following treatment. Changes in transporter protein expression were associated with significant decreases in duodenal iron transport and serum iron. In THP-1 macrophages, ferroportin protein levels were decreased by 300 and 1000 nmol/L hepcidin. In contrast, ferroportin protein expression was unaltered in intestinal Caco-2 cells following exposure to hepcidin. However, iron efflux from Caco-2 cells was significantly inhibited in the presence of hepcidin, suggesting that the peptide could block ferroportin function in these cells. We conclude that hepcidin regulates the release of iron from both enterocytes and macrophages. However, taken together with our previous work, it is apparent that macrophages are more sensitive than enterocytes to a hepcidin challenge.

^* To whom correspondence should be addressed. E-mail: paul.a.sharp{at}kcl.ac.uk.

Manuscript received 1 December 2008. Initial review completed 4 February 2009. Revision accepted 26 May 2009.

Published online 23 June 2009.