Article

Two to Tango: Regulation of Mammalian Iron Metabolism

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Cell (Impact Factor: 32.24). 07/2010; 142(1):24-38. DOI: 10.1016/j.cell.2010.06.028
Source: PubMed

ABSTRACT

Disruptions in iron homeostasis from both iron deficiency and overload account for some of the most common human diseases. Iron metabolism is balanced by two regulatory systems, one that functions systemically and relies on the hormone hepcidin and the iron exporter ferroportin, and another that predominantly controls cellular iron metabolism through iron-regulatory proteins that bind iron-responsive elements in regulated messenger RNAs. We describe how the two distinct systems function and how they "tango" together in a coordinated manner. We also highlight some of the current questions in mammalian iron metabolism and discuss therapeutic opportunities arising from a better understanding of the underlying biological principles.

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Available from: Clara Camaschella, Aug 25, 2014
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    • "j.celrep.2015.12.065 hemochromatosis,'' which is characterized by tissue iron accumulation , iron-mediated injury, and organ dysfunction (Fleming and Ponka, 2012). Mouse models of hereditary hemochromatosis correctly recapitulate various human diseases (Hentze et al., 2010). To avoid iron overload, cells shelter iron in ferritin. "
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    ABSTRACT: The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2–3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239–614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "In mammals the control of the systemic iron regulation relies mainly on hepcidin, which controls iron availability by suppressing ferroportin, the iron exporter (Ganz and Nemeth, 2012). Hepcidin expression, in turn, is regulated by systemic and hepatic iron stores, by erythropoietic activity, ER stress, hypoxia and inflammatory conditions (Hentze et al., 2010), with mechanisms that involve primarily the BMP/SMAD signaling pathway (Babitt et al., 2007). Among the various BMP members, BMP6 is the one dedicated to hepcidin expression, it binds to BMP receptors of type I (ALK2 and 3) and type II (AcvR2 and BMPR2) causing the phosphorylation of SMAD1/5/8 which assemble with SMAD4 and transfer into the nucleus to activate hepcidin Abbreviations: BMP, bone morphogenetic protein, SMAD, small mother against decapentaplegic, STAT, signal transducer and activator of transcription; IL-6, interleukin -6. "
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    ABSTRACT: Heparins are efficient inhibitors of hepcidin expression even in vivo, where they induce an increase of systemic iron availability. Heparins seem to act by interfering with BMP6 signaling pathways that control the expression of liver hepcidin, causing the suppression of SMAD1/5/8 phosphorylation. The anti-hepcidin activity persists also when the heparin anticoagulant property is abolished or reduced by chemical reactions of oxidation/reduction (glycol-split, Gs-Heparins) or by high sulfation (SS-Heparins), but the structural characteristics needed to optimize this inhibitory activity have not been studied in detail. To this aim we analyzed three different heparins (Mucosal Heparin, the Glycol split RO-82, the partially desulfated glycol-split RO-68 and the oversulfated SSLMWH) and separated them in fractions of molecular weight in the range 4–16 kD. Since the distribution of the negative charges in heparins contributes to the activity, we produced 2-O- and 6-O-desulfated heparins. These derivatives were analyzed for the capacity to inhibit hepcidin expression in hepatic HepG2 cells and in mice. The two approaches produced consistent results and showed that the anti-hepcidin activity strongly decreases with molecular weight below 7 kD, with high N-acetylation and after 2-O and 6-O desulfation. The high sulfation and high molecular weight properties for efficient anti-hepcidin activity suggest that heparin is involved in multiple binding sites.
    Preview · Article · Jan 2016 · Frontiers in Pharmacology
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    • "The expression of hepcidin (encoded by the HAMP gene) is regulated by iron stores, inflammation, hypoxia, and erythropoiesis, processes that are regulated primarily by the BMP/SMAD and JAK/STAT signaling pathways[5] [6]. Many iron-related disorders are associated with altered hepcidin expression[7]. "
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    ABSTRACT: Hepcidin, a master regulator of iron homeostasis, is a promising target in treatment of iron disorders such as hemochromatosis, anemia of inflammation, and iron-deficiency anemia. We previously reported that black soybean seed coat extract could inhibit hepcidin expression. Based on this finding, we performed a screen in cultured cells in order to identify the compounds in black soybeans that inhibit hepcidin expression. We found that the dietary flavonoid myricetin significantly inhibited the expression of hepcidin both in vitro and in vivo. Treating cultured cells with myricetin decreased both HAMP mRNA levels and promoter activity by reducing SMAD1/5/8 phosphorylation. This effect was observed even in the presence of bone morphogenic protein-6 (BMP6) and interleukin-6 (IL-6), two factors that stimulate hepcidin expression. Furthermore, mice that were treated with myricetin (either orally or systemically) had reduced hepatic hepcidin expression, decreased splenic iron levels, and increased serum iron levels. Notably, myricetin-treated mice increased red blood cell counts and hemoglobin levels. In addition, pretreating mice with myricetin prevented LPS-induced hypoferremia. We conclude that myricetin potently inhibits hepcidin expression both in vitro and in vivo, and this effect is mediated by altering BMP/SMAD signaling. These experiments highlight the feasibility of identifying and characterizing bioactive phytochemicals to suppress hepcidin expression. These results also suggest that myricetin may represent a novel therapy for treating iron deficiency–related diseases.
    Full-text · Article · Nov 2015
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