The role of hepcidin in regulating intestinal iron absorption

Lead Research Organisation: King's College London
Department Name: Nutritional Sciences

Abstract

Iron deficiency anaemia is the most common nutritional deficiency affecting 2 billion people worldwide. While the majority of those affected live in the developing world, up to 30% of women of childbearing age in the UK are also iron deficient. It is estimated that the treatment of ailments associated with iron deficiency costs the NHS approximately £25 million per year. Conventional treatment for iron deficient patients relies on supplements containing relatively high doses of iron. While these supplements improve iron status in the long term, they can cause gastro-intestinal disturbances and are therefore poorly tolerated by some patients. The development of improved treatment regimes would therefore benefit those on supplementation therapy. Hepcidin, a regulatory peptide that controls iron absorption, might be a target for the development of such alternative therapies. As a first step in exploring this possibility, our study will establish a better understanding of the mechanisms by which hepcidin interacts (i) with intestinal epithelial cells to regulate dietary iron absorption and (ii) with macrophages which recover iron from dead red blood cells so that it can be re-used for the production of erythrocyte haemoglobin . These preliminary studies will highlight important cellular mechanisms that can be explored further as possible targets for therapeutic intervention.

Technical Summary

Iron deficiency and associated anaemia represent major global health problems - current estimates suggest that up to 2 billion people (mainly in the developing world) are affected. In the UK, while full-blown anaemia is relatively rare it is thought that up to 30% of pre-menopausal women have low iron stores. This places a major burden on the NHS - the cost of treating iron deficiency is estimated to be £25 million per annum. Current treatment involves the use of high dose iron supplements which in a number of cases are poorly tolerated. At present, alternative therapies remain elusive, though one possible target might be the iron regulatory peptide hepcidin. In order to develop this possibility it is essential to gain a better understanding of the cellular mechanisms involved in the hepcidin regulatory pathway. With this aim in mind, the current proposal will explore the interactions between hepcidin and the intestinal epithelium (responsible for regulating dietary iron absorption). The timecourse of events following exposure to hepcidin will be determined and will include measurement of iron transport across the epithelium and changes in the expression of key genes and proteins involved in intestinal iron metabolism. Possible regulatory mechanisms involved in the response to hepcidin at the cellular level will also be explored using genomic technology. Together these studies will give us a better understanding of the mechanisms by which the major regulator of body iron metabolism operates. This information is essential if the hepcidin pathway is to be exploited as an avenue for improved treatment of people with iron deficiency and iron deficiency anaemia.
 
Description Our work was the first to demonstrate that there are cell-specific differences in the actions of the iron regulatory hormone hepcidin in controlling iron metabolism in intestinal enterocytes and macrophages.



We have demonstrated that upon its release, hepcidin rapidly targets macrophages reducing the rate of iron recycling (within 1-4 hours following exposure). Duodenal enterocytes are less sensitive to the initial rise in hepcidin levels and iron absorption is not altered within this time frame.



Prolonged exposure to hepcidin, for 24-72h, down-regulates intestinal iron transporter expression and iron absorption.



The fact that macrophages respond more acutely than enterocytes to hepcidin is fully consistent with their paramount importance in maintaining body iron homeostasis.



We demonstrated that in the context of inflammation and hypoxia cross-talk between macrophages and hepatocytes is important in controlling the expression of hepcidin. This has an important bearing on our understanding of the mechanisms that modulate the production of this iron regulatory hormone.
Exploitation Route Our data may be useful in future drug design, for example, the generation of synthetic hepcidin-like molecules to regulate selectively either intestinal iron absorption or macrophage iron recycling. This might form the basis of improved treatment regimes that would benefit patients on iron supplementation therapy or suffering from tissue iron loading disorders.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology