The iron-regulatory hormone hepcidin: a possible therapeutic target?

Pharmacol Ther. 2015 Feb;146:35-52. doi: 10.1016/j.pharmthera.2014.09.004. Epub 2014 Sep 7.

Abstract

The maintenance of stable extracellular and intracellular iron concentrations requires the coordinated regulation of iron transport into plasma. Iron is a fundamental cofactor for several enzymes involved in oxidation-reduction reactions. The redox ability of iron can lead to the production of oxygen free radicals, which can damage various cellular components. Therefore, the appropriate regulation of systemic iron homeostasis is decisive in vital processes. Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. It is synthesized in hepatocytes and in other cells and released into the circulation. It inhibits the release of iron from enterocytes of the duodenum and from macrophages by binding to the iron exporter protein, ferroportin (FPN). FPN is a transmembrane protein responsible for iron export from cells into the plasma. Hepcidin is internalized with FPN and both are degraded in lysosomes. The hepcidin-FPN axis is the principal regulator of extracellular iron homeostasis in health and disease. Its manipulation via agonists and antagonists is an attractive and novel therapeutic strategy. Hepcidin agonists include compounds that mimic the activity of hepcidin and agents that increase the production of hepcidin by targeting hepcidin-regulatory molecules. The inhibition of hepcidin could be a potentially attractive therapeutic strategy in patients suffering from anaemia or chronic inflammation. In this review, we will summarize the role of hepcidin in iron homeostasis and its contribution to the pathophysiology of inflammation and iron disorders. We will examine emerging new strategies that modulate hepcidin metabolism.

Keywords: Hepcidin; Homeostasis; Inflammation; Iron; Redox.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cardiovascular Diseases / metabolism
  • Cation Transport Proteins / metabolism
  • Cytoprotection / physiology
  • Hepcidins / chemistry
  • Hepcidins / metabolism*
  • Humans
  • Iron / metabolism
  • Liver / metabolism

Substances

  • Cation Transport Proteins
  • Hepcidins
  • metal transporting protein 1
  • Iron