ferroportin
Summary
Ferroportin is the only known cellular iron exporter in humans, responsible for transporting iron from enterocytes, macrophages, and hepatocytes into the bloodstream. It is negatively regulated by hepcidin, the master regulator of systemic iron homeostasis. Mutations in ferroportin cause ferroportin disease, a form of hereditary hemochromatosis.
Detail
Ferroportin (SLC40A1) is expressed on the basolateral membrane of duodenal enterocytes, macrophages (especially splenic and hepatic Kupffer cells), hepatocytes, and placental cells. It exports Fe2+ from these cells into plasma, where it is oxidized to Fe3+ by ferroxidases (hephaestin in enterocytes, ceruloplasmin systemically) and loaded onto transferrin for transport to tissues, primarily the bone marrow for erythropoiesis.
Regulation: Hepcidin, a peptide hormone produced by the liver in response to iron overload, inflammation (via IL-6), and infection, binds ferroportin and induces its internalization and lysosomal degradation. This decreases iron export, trapping iron within enterocytes and macrophages, leading to decreased serum iron. This mechanism underlies anemia of chronic disease/inflammation, where elevated hepcidin sequesters iron despite adequate body stores.
Clinical significance: - Hereditary hemochromatosis type 4 (ferroportin disease): autosomal dominant mutations in SLC40A1. Two phenotypes: (1) loss-of-function mutations causing ferroportin to be trapped intracellularly, leading to iron accumulation predominantly in macrophages (reticuloendothelial iron loading) with high ferritin but normal-to-low transferrin saturation early in disease; (2) gain-of-function mutations that make ferroportin resistant to hepcidin-induced degradation, causing a phenotype more similar to classic HFE hemochromatosis with parenchymal iron loading and elevated transferrin saturation. - Anemia of chronic disease: inflammation-driven hepcidin upregulation suppresses ferroportin, causing functional iron deficiency despite normal/high iron stores (high ferritin, low serum iron, low TIBC). - Iron deficiency anemia: decreased hepcidin allows increased ferroportin activity to maximize iron absorption. - Therapeutic target: hepcidin agonists/antagonists and ferroportin inhibitors are being explored for treating iron overload disorders and anemia of inflammation.
High-yield boards association: Remember the hepcidin-ferroportin axis for distinguishing anemia of chronic disease (high hepcidin, low ferroportin activity, iron trapped in macrophages) from other anemias, and for understanding hemochromatosis subtypes beyond the classic HFE-related type 1.
Sources
- First Aid for the USMLE Step 1
- Robbins Basic Pathology
- Harrison's Principles of Internal Medicine
- Ganong's Review of Medical Physiology
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