Associate editor: M. CurtisThe iron-regulatory hormone hepcidin: A possible therapeutic target?
Introduction
Iron is a fundamental cofactor for several enzymes involved in oxidation–reduction reactions due to its ability to exist in two ionic forms: ferrous (Fe + 2) and ferric (Fe + 3) iron. However, the redox ability of iron can lead to the production of oxygen free radicals, which can damage various cellular components. For this reason, iron levels in tissues must be tightly regulated (Ganz, 2013). Various molecules are involved in iron uptake and storage by hepatocytes and its export from hepatocytes, and systems describing the iron cycle have evolved. The discovery of the iron-regulating role of the hormone hepcidin, followed by the elucidation of its mechanism of action has led to better understanding of the physiopathology of human iron disorders (Munoz-Bravo et al., 2013, Waldvogel-Abramowski et al., 2014) and offers new clinical potential in terms of diagnosis and therapy. Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Knowledge on how hepcidin exerts its regulatory function and on the molecular processes that regulate hepcidin production is largely based on animal and in vitro studies. Hepcidin is a peptide secreted predominantly from hepatocytes. It down-regulates ferroportin, the only known iron exporter, and therefore inhibits iron efflux from duodenal enterocytes, macrophages and hepatocytes into the bloodstream (Ganz & Nemeth, 2012). Hepcidin expression is regulated positively by body iron load. Although the underlying mechanism of iron-regulated hepcidin expression has not been fully elucidated, several proteins have been identified that participate in this process. 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 to modulate hepcidin metabolism. The therapeutic manipulation of hepcidin activity may become an important approach in cardiovascular and metabolic disorders.
Section snippets
Iron distribution
The total amount of iron in a 70-kg adult is approximately 4 g, of which two thirds is the iron in red blood cells and 300 mg is in the myoglobin of muscles. The majority of this iron comes from the recycling of senescent erythrocytes by macrophages of the reticulo-endothelial system (about 20 mg/day) (Gudjoncik et al., 2014). Most of the iron in plasma is directed to the bone marrow for erythropoiesis. More than 2 million new erythrocytes are produced every second by the bone marrow, requiring a
Iron deficiency
The symptoms and signs of iron deficiency are partly explained by the presence of anaemia. Iron deficiency will result from any condition in which dietary iron intake does not meet the body's demands; for this reason, rapidly growing children and premenopausal women are at the highest risk. Iron deficiency caused by dietary insufficiency is usually secondary to intestinal blood loss. Congenital and acquired abnormalities of the intestinal epithelium can also result in iron deficiency. The
The liver: the main regulator of iron metabolism and producer of iron-regulatory proteins (Fig. 1)
The liver is the central regulator of systemic iron balance. Hepatocytes not only store iron, but also play a crucial role in iron metabolism by producing Tf, the iron carrier protein, and hepcidin, a hormone involved in regulating iron metabolism. As we reported previously, hepcidin is mainly synthesized in hepatocytes, secreted from hepatocytes, and excreted through the kidney. Schematically, extracellular circulating iron in the plasma is present as soluble Tf-bound iron, and when there is
Levels of hepcidin
Hepcidin was discovered by three laboratories working independently (Krause et al., 2000, Park et al., 2001, Pigeon et al., 2001). The laboratory of Tomas Ganz invented the name hepcidin, because the gene is highly expressed in the liver (hep-) and was found to possess some microbicidal activity (-cidin). The bacteriostatic effects of iron-binding proteins had already been recognized in the 1940s. It was noted that specific iron-binding proteins in egg white (ovotransferrin) and blood
Sources of extrahepatic hepcidin
Apart from hepatocytes, which are the main source of circulating hepcidin, other cell types such as macrophages, adipocytes, and heart and stomach cells express hepcidin mRNA, but at a lower level. While extrahepatic hepcidin expression is becoming established, the physiological role of hepcidin in extrahepatic tissues is only partially understood. Extrahepatic hepcidin production may play a role in the local regulation of iron fluxes.
Importance of the hepcidin-ferroportin interaction (Fig. 4)
The interaction of hepcidin with FPN provides a mechanism for coordinating the entry of iron into the plasma with iron utilization and storage. Recent advances in understanding the molecular mechanisms of hepcidin regulation in particular in relationship with FPN and its targets came from studying patients with a genetic iron-overloaded disorder such as haemochromatosis. These patients present mutations in genes that encode different proteins and they have low hepcidin levels relative to iron
Hepcidin: master regulator of iron metabolism
When iron stores are adequate or high, the liver produces hepcidin, which circulates to the small intestine. FPN molecules are expressed on the basolateral membranes of enterocytes, and they transport iron from enterocytes to plasma transferrin. Hepcidin causes FPN to be internalized, thus blocking the pathway for the transfer of iron from enterocytes or macrophages to plasma. Macrophages export Fe2+ from their plasma membrane via FPN, in a process coupled with the re-oxidation of Fe2+ to Fe3+
Regulation of hepcidin expression (Fig. 5)
The expression of hepcidin is dependent on opposing signalling pathways: the combined effects of the various pathways will determine hepcidin levels. The systemic factors that alter hepcidin expression, such as anaemia or inflammation, are well established. However, the mechanism by which hepcidin production is regulated at the molecular level is still unclear.
HFE, the gene mutated in the most common form of hereditary haemochromatosis, plays a role in monitoring body iron status and then
Pharmacology: targeting the hepcidin–ferroportin axis (Table 1)
The hepcidin–FPN axis is the principal regulator of extracellular iron homeostasis in health and disease. Its manipulation via agonistic and antagonistic pathways 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. Advances are being made in this area through the development of small molecule modulators of hepcidin regulation
Hepcidin: an endogenous cytoprotective agent in cardiovascular pathophysiology and possible therapeutic targets?
The presence of hepcidin in body fluids raises questions about its function within these compartments. The role of hepcidin as an antimicrobial agent is well established (Verga Falzacappa & Muckenthaler, 2005) and given that body fluids play an important role in the natural defences against inflammation, it is conceivable that hepcidin plays a role in cellular protection.
It is now well established that LPS mediates its effects through TLR4, for the induction of pro-inflammatory genes. LPS,
Conclusion
Iron is the only micronutrient known to have a regulatory hormone, hepcidin, that responds to both nutrient status and infections. Hepcidin acts to block both iron absorption in the gut and iron release from macrophages through a common mechanism. The discovery of the hormonal iron-regulating role of hepcidin, followed by the elucidation of its mechanism of action has led to better understanding of the physiopathology of human iron disorders. Positive regulators of hepcidin, which lead to
Funding
This work was supported by grants from the French Ministry of Research, from the Institut National de la Santé et de la Recherche Médicale (INSERM) and from the Regional Council of Burgundy.
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
The authors wish to thank Martine Goiset for secretarial assistance and Philip Bastable for English assistance. The authors acknowledge the essential technical contribution of Andre Bouchot (Histologie — Plateau Technique Imagerie Cellulaire).
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