The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis

Abstract

Ferroportin (SLC40A1) is an iron transporter postulated to play roles in intestinal iron absorption and cellular iron release. Hepcidin, a regulatory peptide, binds to ferroportin and causes it to be internalized and degraded. If ferroportin is the major cellular iron exporter, ineffective hepcidin function could explain manifestations of human hemochromatosis disorders. To investigate this, we inactivated the murine ferroportin (Fpn) gene globally and selectively. Embryonic lethality of Fpn(null/null) animals indicated that ferroportin is essential early in development. Rescue of embryonic lethality through selective inactivation of ferroportin in the embryo proper suggested that ferroportin has an important function in the extraembryonic visceral endoderm. Ferroportin-deficient animals accumulated iron in enterocytes, macrophages, and hepatocytes, consistent with a key role for ferroportin in those cell types. Intestine-specific inactivation of ferroportin confirmed that it is critical for intestinal iron absorption. These observations define the major sites of ferroportin activity and give insight into hemochromatosis.

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

“…Additionally, we also recently found reduced level of FPN in breast cancers, associated with poor prognosis in breast cancer patients [11,30]. To keep the balance of systemic iron metabolism, FPN is predominantly regulated by hepcidin through binding and inducing ubiquitin-dependent proteasomal degradation of FPN protein [6]. FPN concentration is also subjected to the regulation by the iron responsive element (IRE)/iron responsive protein (IRP) system at the post-transcriptional level [15,62,63].…”

“…For animals, 8-week-old female C57BL/6 mice were purchased from the Vital River Laboratories (Beijing, China), and FPN1-floxed and LysM-Cre mice with the 129/SvEvTac background were provided by Dr. Fudi Wang [6,[26][27][28]. LysM-Cre mice were mated with FPN1 flox/flox mice to create the strain in which FPN was inactivated in macrophages.…”

“…In fact, iron disorders in the form of either iron deficiency or overload cause detrimental impacts on cells [3][4][5]. Mammalian iron homeostasis is concertedly regulated through the hepcidin-ferroportin (FPN) axis that fundamentally governs iron absorption, transport, storage and utilization [3,6]. Iron needs the sole known iron exporter, FPN, to shuttle out of the cells.…”

The role of lysosomes in iron metabolism and recycling

“…In the enterocyte, iron is liberated by heme oxygenase 1 (Hmox 1) (Dunn et al, 2007). Iron is then transported away from the basolateral membrane of the enterocyte and from macrophages, by ferroportin 1, which is expressed in all iron-exporting cells and plays a critical role in the regulation of iron-export to the bloodstream (Donovan et al, 2005, Troadec et al, 2010.…”

Differential regulation of iron homeostasis during human macrophage polarized activation

“…Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16].…”