Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter

Abstract

Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMTi. A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

“…Ferroportin (ferroportin 1, also termed Ireg1, MTP1, and SLC40A1) is a cell surface transmembrane protein and is the only known export protein for nonheme iron (10–12). Ferroportin is expressed at high concentrations on duodenal enterocytes, placenta, hepatocytes, and macrophages (10–12) and is an essential component of systemic iron homeostasis (13).…”

“…Ferroportin is expressed at high concentrations on duodenal enterocytes, placenta, hepatocytes, and macrophages (10–12) and is an essential component of systemic iron homeostasis (13). Ferroportin is regulated by at least three mechanisms: transcriptional regulation, which controls levels (14) and splice variants (15) of the messenger RNA (mRNA); translational control, which regulates ferroportin through an iron-regulatory element in the 5′ untranslated region of ferroportin mRNA (16); and organismal iron status, which regulates ferroportin-mediated iron efflux through a direct interaction of ferroportin with the peptide hormone hepcidin (17).…”

Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element

“…Iron needs the sole known iron exporter, FPN, to shuttle out of the cells. [7] As a transmembrane transporter, FPN is responsible for dietary iron absorption in enterocytes of small intestine, and also controls iron release from macrophages and other cells [8,9]. High levels of FPN lead to enforced dietary iron absorption and egress from storage out of cells including macrophages and hepatocytes, which is associated with several types of diseases, such as hereditary hemochromatosis and β-thalassemia caused by iron overload [5].…”

Altered expression of the iron transporter Nramp1 (Slc11a1) during fetal development of the retinal pigment epithelium in microphthalmia-associated transcription factor Mitfmi and Mitfvitiligo mouse mutants

“…Fe +2 in the labile iron pool may be bound by ferritin, an intracellular ironsequestering protein that functions in iron storage and the protection of cells from iron toxicity. Alternatively, iron may be exported through the RPE apical membrane to the neural retina by the divalent iron ion exporter ferroportin (IREG1) (Donovan et al, 2000). In macrophages, Fe +2 is transported into or out of phagosomes by the iron transporter Nramp1 (Nevo and Nelson, 2006).…”