Journal Article

An essential cell-autonomous role for hepcidin in cardiac iron homeostasis

Wolna, Magda, Brescia, Marcella, Chung, Yu Jin, Ball, Vicky, Lakhal-Littleton, Samira, Davies, Benjamin, Christian, Helen C, Diaz, Rebeca, Heather, Lisa C, Clarke, Kieran, Robbins, Peter A, Santos, Ana, Biggs, Daniel

2016

Overview

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain. Many proteins inside cells require iron to work properly, and so this mineral is an essential part of the diets of most mammals. However, because too much iron in the body is also bad for health, mammals possess several proteins whose role is to maintain the balance of iron. Two proteins in particular, called hepcidin and ferroportin, are thought to be important in this process. Some ferroportin is found in the cells that line the gut (where iron is absorbed into the body) and is required to release this iron into the bloodstream. It is also found in the spleen, which is where iron is removed from old red blood cells so that it can be recycled. The liver produces hepcidin to control when ferroportin is active in the gut and spleen. Both hepcidin and ferroportin are also found in heart cells. In 2015, a study reported that that heart ferroportin plays an important role in heart activity. However, it was not clear what role hepcidin plays in this organ. Now, Lakhal-Littleton et al. – including many of the researchers from the previous work – have genetically engineered mice such that they specifically lacked heart hepcidin, or had a version of ferroportin in their heart that does not respond to hepcidin. The experiments show that these changes caused fatal heart failure in the mice because ferroportin releases iron from heart cells in an uncontrolled manner. Lakhal-Littleton et al. were able to prevent heart failure by injecting the animals with iron directly into the bloodstream. These findings show that hepcidin produced outside the liver has a role in controlling the levels of iron in the body’s organs. Other organs such as the brain, kidney and placenta all have their own forms of hepcidin and ferroportin; further work could investigate the roles of these proteins. Finally, another challenge for the future will be to test whether new drugs that are being developed to block or mimic hepcidin from the liver have the potential to treat heart conditions in humans.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animal models / Animals / Biochemistry / Cardiomyocytes / Cation Transport Proteins - genetics / Cation Transport Proteins - metabolism / Cell Biology / Clonal deletion / Diet / Enzymes / Ferroportin / Gene expression / Gene Knock-In Techniques / Gene Knockout Techniques / Heart / Heart diseases / Hepcidin / Hepcidins - genetics / Hepcidins - metabolism / Homeostasis / Hypotheses / Iron / Iron - metabolism / Iron deficiency / Kidneys / Liver / Mammals / Metabolism / Mice / Muscle contraction / Myocytes, Cardiac - metabolism / Nutrient deficiency / Proteins / Rodents / Spleen