is a 12-transmembrane domain protein, belonging to the major facilitator superfamily of transporters of small molecules, that is localized to the plasma membrane
. Human Ferroportin has a theoretical molecular weight of 62.5 kDa. Ferroportin (FPN1 or SLC40A1) functions as an iron-regulated transporter (highly expressed in placenta, intestine, muscle, spleen, macrophages etc.) and is the receptor for the iron-regulatory hormone, hepcidin. In iron metabolism, FPN1 plays a key role in intestinal iron absorption as well as cellular iron release and mediates iron absorption in the presence of ferroxidases, hephaestin
(HP) and/or ceruloplasmin
(CP). FPN1 is implicated in iron export from duodenal epithelial cells and in the transfer of iron between maternal and fetal circulation. FPN1 transports iron in the ferrous form whereas plasma transferrin
only binds iron's ferric form. Ferroxidases are key players in oxidizing iron transported by FPN1 and without the activity of ferroxidases, FPN1 is internalized followed by degradation. While other cell types utilize the circulating or GPI-linked multicopper ferroxidase CP for FPN1, intestinal cells utilize a membrane-bound HP, a paralog of CP that also show interaction with FPN1 (1).
FPN1 regulation is dependent on the cell type and involves transcriptional, posttranscriptional, and posttranslational mechanisms including hepcidin-mediated endocytosis and proteolysis. Hepcidin controls the concentration of FPN1 in the membrane, with hepcidin deficiency resulting in iron overload (high iron) and hepcidin excess leading to iron restriction and anemia (2). Ferroportin disease or hemochromatosis type 4 (HFE4) is associated with distinct FPN1 variants with either reduced FPN1 cell surface expression/iron export capacity or hepcidin resistance and iron overload (3, 4).
1. De Domenico I, Ward DM, Kaplan J. (2011) Hepcidin and ferroportin: the new players in iron metabolism. Semin Liver Dis. 31(3):272-9. PMID: 21901657
2. Drakesmith H, Nemeth E, Ganz T. (2015) Ironing out Ferroportin. Cell Metab. 22(5):777-87. PMID: 26437604
3. Pietrangelo A. (2017) Ferroportin disease: pathogenesis, diagnosis and treatment. Haematologica. 102(12):1972-1984. PMID: 29101207
4. Vlasveld LT, Janssen R, Bardou-Jacquet E, Venselaar H, Hamdi-Roze H, Drakesmith H, Swinkels DW. (2019) Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features. Pharmaceuticals (Basel). 12(3). pii: E132. PMID: 31505869