Ferroportin (FPN) is the only known cellular exporter of iron in vertebrates. Iron is essential for processes like oxygen transport and DNA synthesis, but it can be toxic in excess, so its levels must be tightly managed. FPN is the final common pathway for iron to leave a cell and enter the bloodstream, making it the central mediator of systemic iron balance. The protein’s activity dictates how much iron is absorbed from the diet and how much is recycled from old blood cells, controlling the iron available for the entire organism.
FPN’s Function in Cellular Iron Release
Ferroportin is a transmembrane protein embedded in the outer membrane of specific cells, acting as a channel for iron to pass through. Iron inside the cell moves across this protein and is released into the extracellular space, typically the bloodstream. This export mechanism is the only route by which iron can exit the cells that handle the body’s largest iron flows.
FPN is expressed most prominently in three cell types responsible for systemic iron distribution. FPN is found on the basolateral membrane of duodenal enterocytes, the cells lining the small intestine that absorb dietary iron. Iron absorbed from food must be exported by FPN into the circulation for use by the rest of the body.
FPN is also highly expressed on macrophages, especially those in the liver and spleen. These cells break down old red blood cells, releasing large amounts of iron. FPN then exports this recycled iron, which accounts for the majority of the iron that enters the plasma daily.
FPN is also located on hepatocytes, the main cells of the liver, which serve as the body’s primary iron storage site. When iron demands increase, FPN facilitates the release of stored iron back into the blood. This ensures a constant supply of iron is available to tissues like the bone marrow for new red blood cell production.
How Iron Export is Controlled
The regulation of Ferroportin activity is managed almost entirely by hepcidin, a small peptide hormone that acts as the body’s master iron regulator. Hepcidin is synthesized primarily by the liver and secreted into the bloodstream in response to high iron levels and inflammation. This hormone acts as a negative feedback loop to decrease the amount of iron circulating in the body.
Hepcidin travels through the blood and binds directly to FPN on the surface of iron-exporting cells. This binding causes modifications that tag the FPN protein for destruction. The tagged FPN is then pulled from the cell membrane into the cell’s interior through endocytosis.
Once internalized, FPN is rapidly degraded within the cell’s lysosomes, effectively removing the iron export pathway from the cell surface. The resulting lack of functional FPN means that iron cannot exit the cell and becomes trapped inside.
This hepcidin-mediated degradation precisely controls systemic iron levels. When iron levels are high, hepcidin increases, FPN is destroyed, and iron export stops, preventing overload. When iron levels are low, hepcidin decreases, FPN remains on the cell surface, and iron export is maximized to restore circulating iron.
FPN Dysfunction and Associated Diseases
Malfunction of the Ferroportin protein disrupts the hepcidin-FPN regulatory axis, leading to serious disorders of iron metabolism. These dysfunctions fall into two categories based on how the FPN protein is affected. A genetic mutation in the SLC40A1 gene, which codes for FPN, can cause the protein to be less effective at exporting iron or prevent it from moving to the cell surface.
This mutation leads to classic Ferroportin Disease, or Hereditary Hemochromatosis Type 4A. Iron becomes trapped inside macrophages and liver cells because it cannot be released into the plasma. Circulating iron levels remain low, yet iron accumulates within specific organs, particularly the liver, leading to a unique pattern of iron loading.
A different class of mutation causes FPN to be resistant to hepcidin regulation. This means FPN remains on the cell surface and continues to export iron even when hepcidin levels are high, resulting in an overactive FPN (Hemochromatosis Type 4B).
The unchecked iron export floods the plasma with iron, causing systemic iron overload that mimics other forms of hereditary hemochromatosis. The body accumulates excessive iron because the regulatory brake—the hepcidin-FPN interaction—is broken, leading to progressive tissue damage.