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Summary: Iron deficiency (ID) and iron‐deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults. IDA is usually treated by oral iron supplementation, typically using iron salts (e.g. FeSO4); however, dosing at several‐fold above the RDA may be required due to less efficient absorption. Excess enteral iron causes adverse gastrointestinal side effects, thus reducing compliance, and negatively impacts the gut microbiome. Recent research has sought to identify new iron formulations with better absorption so that lower effective dosing can be utilized. This article outlines emerging research on oral iron supplementation and focuses on molecular mechanisms by which different supplemental forms of iron are transported across the intestinal epithelium and whether these transport pathways are subject to regulation by the iron‐regulatory hormone hepcidin. [ABSTRACT FROM AUTHOR]

Identification of biological mediators in sarcopenia is pertinent to the development of targeted interventions to alleviate this condition. Iron is recognized as a potent pro-oxidant and a catalyst for the formation of reactive oxygen species in biological systems. It is well accepted that iron accumulates with senescence in several organs, but little is known about iron accumulation in muscle and how it may affect muscle function. In addition, it is unclear if interventions which reduced age-related loss of muscle quality, such as calorie restriction, impact iron accumulation. We investigated non-heme iron concentration, oxidative stress to nucleic acids in gastrocnemius muscle and key indices of sarcopenia (muscle mass and grip strength) in male Fischer 344 X Brown Norway rats fed ad libitum (AL) or a calorie restricted diet (60% of ad libitum food intake starting at 4 months of age) at 8, 18, 29 and 37 months of age. Total non-heme iron levels in the gastrocnemius muscle of AL rats increased progressively with age. Between 29 and 37 months of age, the non-heme iron concentration increased by approximately 200% in AL-fed rats. Most importantly, the levels of oxidized RNA in gastrocnemius muscle of AL rats were significantly increased as well. The striking age-associated increase in non-heme iron and oxidized RNA levels and decrease in sarcopenia indices were all attenuated in the calorie restriction (CR) rats. These findings strongly suggest that the age-related iron accumulation in muscle contributes to increased oxidative damage and sarcopenia, and that CR effectively attenuates these negative effects.

The transmembrane protein ferroportin (Fpn) is essential for iron efflux from the liver, spleen, and duodenum. Fpn is regulated predominantly by the circulating iron regulatory hormone hepcidin, which binds to cell surface Fpn, initiating its degradation. Accordingly, when hepcidin concentrations decrease, Fpn levels increase. A previous study found that Fpn levels were not elevated in copper-deficient (CUD) mice that had anemia, a condition normally associated with dramatic reductions in hepcidin. Lack of change in Fpn levels may be because CuD mice do not display reduced concentrations of plasma iron (holotransferrin), a modulator of hepcidin expression. Here, we examined Fpn protein levels and hepcidin expression in CuD rats, which exhibit reduced plasma iron concentrations along with anemia. We also examined hepcidin expression in anemic CuD mice with normal plasma iron levels. We found that CuD rats had higher liver and spleen Fpn levels and markedly lower hepatic hepcidin mRNA expression than did copper-adequate (CuA) rats. In contrast, hepcidin levels did not differ between CuD and CuA mice. To examine potential mediators of the reduced hepcidin expression in CuD rats, we measured levels of hepatic transferrin receptor 2 (TfR2), a putative iron sensor that links holotransferrin to hepcidin production, and transcript abundance of bone morphogenic protein 6 (BMP6), a key endogenous positive regulator of hepcidin production. Diminished hepcidin expression in CuD rats was associated with lower levels of TfR2, but not BMP6. Our data suggest that holotransferrin and TfR2, rather than anemia or BMP6, are signals for hepcidin synthesis during copper deficiency. doi: 10.3945/jn.109.117077

Interactions between the essential dietary metals, iron and copper, have been known for many years. This review highlights recent advances in iron-copper interactions with a focus on tissues and cell types important for regulating whole-body iron and copper homeostasis. Cells that mediate dietary assimilation (enterocytes) and storage and distribution (hepatocytes) of iron and copper are considered, along with the principal users (erythroid cells) and recyclers of red cell iron (reticuloendothelial macrophages). Interactions between iron and copper in the brain are also discussed. Many unanswered questions regarding the role of these metals and their interactions in health and disease emerge from this synopsis, highlighting extensive future research opportunities. Key words: anemia, ceruloplasmin, copper, hephaestin, iron doi: 10.1111/j.1753-4887.2010.00271.x

Matriptase-2 is a recently identified membrane-bound, cell-surface serine protease expressed primarily in liver. Mutations in matriptase-2 in mice and humans cause iron-deficiency anemia that responds poorly to iron therapy. The poor response results from an inability to decrease hepcidin production during iron deficiency. Cell culture studies reveal that matriptase-2 inhibits hepcidin induction by cleaving membrane hemojuvelin, a potent activator of hepcidin transcription. As a novel suppressor of hepcidin expression, matriptase-2 emerges as a possible candidate for therapeutic interventions aimed at treating disorders of iron metabolism.

The transmembrane protein ferroportin is highly expressed in tissue macrophages, where it mediates iron export into the bloodstream. Although ferroportin expression can be controlled post-transcriptionally through a 5' iron-responsive element in its mRNA, various studies have documented increased ferroportin mRNA levels in response to iron, suggesting transcriptional regulation. We studied the effect of iron loading on levels of macrophage ferroportin mRNA, as well as heterogeneous nuclear RNA (hnRNA), the immediate product of ferroportin gene transcription. J774 cells, a mouse macrophage cell line, were incubated for 0, 3, 6, 9, 12, and 24 h in medium supplemented or not with 200 [micro]mol/L iron. Quantitative RT-PCR was used to measure steady-state levels of ferroportin mRNA and hnRNA. Ferroportin mRNA levels increased by 12 h after iron treatment, reaching 6 times the control levels after 24 h. Changes in ferroportin mRNA levels were paralleled by similar changes in the levels of ferroportin mRNA. Time course studies of ferroportin mRNA and hnRNA abundance after incubating cells with the transcriptional inhibitor actinomycin D revealed that ferroportin mRNA has a half-life of ~4 h and that iron loading does not stabilize ferroportin mRNA or hnRNA. Collectively, these data are consistent with the hypothesis that iron increases macrophage ferroportin mRNA levels by inducing transcription of the ferroportin gene.

Studies show that the plant polyphenol resveratrol can extend the life span of yeast, worms, flies, and fish. It also mitigates the metabolic dysfunction of mice fed high-fat diets. Resveratrol appears to mediate these effects partly by activating SIRT1, a deacetylase enzyme that regulates the activity of several transcriptional factors and enzymes responsive to nutrient availability. However, few foods contain resveratrol and humans metabolize it extensively, resulting in very low systemic bioavailability. Substantial research effort now focuses on identifying and testing more bioavailable and potent activators of SIRT1 for use as pharmacologic interventions in aging and age-related disorders.

Erythroid cells of the bone marrow, the most avid consumers of iron in the body, acquire ferric ([Fe.sup.3+]) iron exclusively via the transferrin cycling pathway. A long-standing fundamental molecular question of how ferric iron is handled in this pathway has been recently resolved by the identification of Steap3 (six-transmembrane epithelial antigen of the prostate 3) as an endosomal ferrireductase needed for efficient utilization of transferrin-delivered iron. Further characterization of Steap3 and other Steap proteins reveals a possible greater role of Steap proteins in iron and copper metabolism. Key words: anemia, cupric reductase, DMT1, ferrireductase

Loss of p53's proper function accounts for over half of identified human cancers. We identified the metal transporter ZIP14 (Zinc-regulated transporter (ZRT) and Iron-regulated transporter (IRT)-like Protein 14) as a p53-regulated protein. ZIP14 protein levels were upregulated by lack of p53 and downregulated by increased p53 expression. This regulation did not fully depend on the changes in ZIP14's mRNA expression. Co-precipitation studies indicated that p53 interacts with ZIP14 and increases its ubiquitination and degradation. Moreover, knockdown of p53 resulted in higher non-transferrin-bound iron uptake, which was mediated by increased ZIP14 levels. Our study highlights a role for p53 in regulating nutrient metabolism and provides insight into how iron and possibly other metals such as zinc and manganese could be regulated in p53-inactivated tumor cells. [ABSTRACT FROM AUTHOR]