Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier
Laura WuA. G. Miriam LeendersSharon CoopermanEsther G. Meyron‐HoltzSophia R. SmithWilliam LandRobert Y. L. TsaiUrs V. BergerZu-Hang ShengTracey A. Rouault
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Ferroportin
Ependymal Cell
DMT1
Transferrin receptor
Immunoelectron microscopy
Homeostasis
Ferroportin
Loss function
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Hepcidin is a peptide hormone produced by the liver, of which secretion is closely related to iron status in the body. However, little is known about the molecular mechanism(s) by which this peptide regulates body iron homeostasis. The purpose of this study was to determine the effects of hepcidin treatment within the physiological concentration range on the expressions of two different iron transporter proteins-ferroportin (FPN) and divalent metal transporter 1 (DMT1). Differentiated Caco-2 intestinal cells and macrophage J774 cells were treated with either synthetic hepcidin or hepcidin-rich fraction separated from human urine at the concentration of 10 nM and 100 nM for 24 hours. Results show that hepcidin treatment in differentiated Caco-2 cells or in J774 cells did not change the level of either FPN mRNA or DMT1 mRNA. On the other hand, hepcidin treatment at the dose of 100 nM significantly decreased the FPN protein levels and DMT1 protein levels in differentiated Caco-2 cells. Similarly, urinary hepcidin treatment (10 nM & 100 nM) also significantly decreased the levels of FPN and DMT1 proteins in J774 macrophage cells. These results showed that hepcidin might play an important role in the regulation of iron homeostasis by lowering the protein levels of iron transporter FPN and DMT1 both in enterocytes and in macrophage cells.
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Homeostasis
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Abstract Background & Aims Ferroportin disease (FD) and hemochromatosis type 4 (HH4) are associated with variants in the ferroportin‐encoding gene SLC40A1 . Both phenotypes are characterized by iron overload despite being caused by distinct variants that either mediate reduced cellular iron export in FD or resistance against hepcidin‐induced inactivation of ferroportin in HH4. The aim of this study was to assess if reduced iron export also confers hepcidin resistance and causes iron overload in FD associated with the R178Q variant. Methods The ferroportin disease variants R178Q andA77D and the HH4‐variant C326Y were overexpressed in HEK‐293T cells and subcellular localization was characterized by confocal microscopy and flow cytometry. Iron export and cytosolic ferritin were measured as markers of iron transport and radioligand binding studies were performed. The hepcidin‐ferroportin axis was assessed by ferritin/hepcidin correlation in patients with different iron storage diseases. Results In the absence of hepcidin, the R178Q and A77D variants exported less iron when compared to normal and C326Y ferroportin. In the presence of hepcidin, the R178Q and C326Y, but not the A77D‐variant, exported more iron than cells expressing normal ferroportin. Regression analysis of serum hepcidin and ferritin in patients with iron overload are compatible with hepcidin deficiency in HFE hemochromatosis and hepcidin resistance in R178Q FD. Conclusions These results support a novel concept that in certain FD variants reduced iron export and hepcidin resistance could be interlinked. Evasion of mutant ferroportin from hepcidin‐mediated regulation could result in uncontrolled iron absorption and iron overload despite reduced transport function.
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Hereditary hemochromatosis
Rubredoxin
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Hereditary hemochromatosis
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Chronic alcohol consumption increases body iron stores. Patients with alcoholic liver disease frequently exhibit iron overload, but mechanisms of its accumulation remain unclear. Many novel iron-regulatory proteins have been identified for several last years, which have improved understanding the underlying some mechanisms of iron overload in alcoholic liver disease. In this paper, the effect of alcohol on hepcidin expression which is a key hormone in the regulation of iron metabolism has been given. Hepcidin regulates of iron metabolism by inhibiting intestinal iron absorption and the release of iron from macrophages. Alcohol was found to down-regulate hepcidin expression in the liver leading to elevated expression of the iron transporter proteins, DMT1 and ferroportin in the duodenum. Ethanol-mediated oxidative stress inhibits C/EBPaz DNA-binding activity and down-regulates hepcidin transcription in the liver. Deregulation of the hormone synthesis may be one of the causes of iron overload during chronic alcohol consumption.
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DMT1
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Ferroportin
DMT1
Hereditary hemochromatosis
Ceruloplasmin
HAMP
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Transferrin receptor
Loss function
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Ferroportin is a transmembrane iron‐export protein that plays an important role in dietary iron absorption and iron recycling from senescent red blood cells. Ferroportin expression increases with tissue iron loading but decreases in response to hepcidin, the circulating iron‐regulatory hormone that binds to ferroportin, causing its internalization and degradation. Hepcidin expression increases with iron loading but decreases during anemia. We examined ferroportin and hepcidin expression in copper‐deficient (CuD) rats, which have elevated liver iron levels but are anemic. We compared CuD and copper‐adequate (CuA) animals (n=4/group) after one month of treatment postweaning. Hemoglobin levels were lower in CuD than in CuA rats (101 vs. 159 g/L). Western blot analysis revealed that ferroportin levels increased in CuD rats relative to CuA rats by 4‐ and 1.6‐fold in liver and spleen, respectively ( P <0.02). Increased ferroportin expression in CuD rat tissues was associated with increased ferroportin transcript abundance, as measured by qRT‐PCR. Copy number of hepatic hepcidin mRNA was more than 50‐fold lower in CuD than CuA rats despite a doubling of liver iron. We conclude that tissue ferroportin levels increase in CuD rats because of diminished hepcidin levels and increased ferroportin mRNA abundance.
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Ferroportin
Transferrin receptor
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Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.
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