Ferritin and intestinal iron absorption: pancreatic enzymes and free iron

M, Linder; Dunn, Virginia; Isaacs, E; Jones, David H.; Lim, Suzanne; Volkom, M Van; Hn, Munro

doi:10.1152/ajplegacy.1975.228.1.196

Cited by 37 publications

(10 citation statements)

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“…Although iron absorption was not measured directly, the increase of ferritin synthesis demonstrates that iron uptake had occurred. The observed increase of ferritin is in agreement with an earlier report that, in a time course similar to our studies following ingestion of 59 Fe, the ingested iron could be found in the enterocytes and in the liver (22). Since FPN1, as well as ferritin, contain an IRE in the 5Ј-untranslated region, iron ingestion should induce the IRP/IRE response to increase translation of both proteins.…”

supporting

confidence: 93%

Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium

Yeh

Yeh²,

Mims³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Yeh KY, Yeh M, Mims L, Glass J. Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium. Am J Physiol Gastrointest Liver Physiol 296: G55-G65, 2009. First published October 30, 2008 doi:10.1152/ajpgi.90298.2008.-Intestinal iron absorption involves proteins located in the brush border membrane (BBM), cytoplasm, and basolateral membrane (BLM) of duodenal enterocytes. Ferroportin 1 (FPN1) and hephaestin (Heph) are necessary for transport of iron out of enterocytes, but it is not known whether these two proteins interact during iron absorption. We first examined colocalization of the proteins by cotransfection of HEK293 cells with pDsRed-FPN1 with pEmGFP-Heph or with the COOH-terminal truncated pEmGFP-Heph⌬43 or -Heph⌬685 and found that FPN1 and Heph with or without the COOH terminus colocalized. In rat duodenal enterocytes, within 1 h of iron feeding prominent migration of FPN1 from the apical subterminal zone to the basal subnuclear zone of the BLM occurred and increased to at least 4 h after feeding. Heph exhibited a similar though less prominent migration after iron ingestion. Analysis using rat duodenal epithelial cell sheets demonstrated that 1) by velocity sedimentation ultracentrifugation, FPN1 and Heph occupied vesicles of different sizes prior to iron feeding and migrated to similar fractions 1 h after iron feeding; 2) by blue native/SDS-PAGE, FPN1, and Heph interacted to form two complexes, one containing dimeric FPN1 and intact Heph and the other consisting of monomeric FPN1 and a Heph fragment; and 3) by immunoprecipitation, anti-Heph or anti-FPN1 antiserum coimmunoprecipitated FPN1 and Heph. Thus the data indicate that FPN1 and Heph migrate and interact during iron feeding and suggest that dimeric FPN1 is associated with intact Heph.DsRed-FPN1; EmGFP-Heph; FPN1 and Heph migration; blue native/ SDS-PAGE; coimmunoprecipitation IRON IS AN ESSENTIAL NUTRIENT absorbed through the duodenal epithelium, and iron homeostasis is achieved by regulation of the absorptive process (20). In the current concept of intestinal iron absorption, dietary iron as Fe 3ϩ is reduced to Fe 2ϩ by the duodenal cytochrome b reductase (Dcytb) (17, 27). The reduced iron is then absorbed through the divalent metal transporter (DMT1) on the brush border membrane (BBM) of duodenal enterocytes (17,27). The Fe 2ϩ then traverses the enterocyte cytoplasm to the basolateral membrane (BLM) where Fe 2ϩ is transported by ferroportin (FPN1) (1, 9, 27) and converted to Fe 3ϩ by the multicopper ferroxidase hephaestin (Heph) (38) before release to transferrin in the systemic circulation. Since Fe 2ϩ is highly reactive and potentially toxic, the molecular mechanisms for handling the absorbed iron as it transverses the enterocyte from BBM to the BLM are important to elucidate. The detailed molecular relationships of the two membrane transporters, DMT1 and FPN1, and the accessory proteins necessary for iron transport remain largely unknown. The Fe 2ϩ transported into the enterocyte may bind to cytosolic...

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supporting

confidence: 93%

Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium

Yeh

Yeh²,

Mims³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Thus, the weanling rats were in the process of estab lishing hepatic iron reserves and, therefore, the demand for dietary iron would be high and efficient iron absorption at the gastro intestinal tract paramount. The adult rats, on the other hand, with substantial iron reserves at the beginning of the period of experimental feeding would have required a small dietary supply of iron in order to maintain iron bal ance [7], It is perhaps worth noting that the impact of riboflavin deficiency on the activ ity of mucosal FMN oxidoreductase was greatest in the weanling animals in which the activity in the deficient rats at day 35 repre sented only 6.6% of activity at day 14, and 3.2% of the activity in the control animals, whereas in the adult deficient animal on day 49 enzyme activity was 27.9% of that at day 14 and 22.3% of control activity.…”

Section: Discussionmentioning

confidence: 99%

“…De spite extensive research into the mechanisms of iron absorption and a wealth of publica tions on the subject, a generally accepted mechanism for iron absorption has not yet been presented [2,14,15]. Recent studies rel egate mucosal ferritin to the role of a 'reser voir' protein, the iron in which is considered to be lost from the body with the sloughing off of the mucosal cell [8], although the pos sibility that iron in mucosal ferritin can still be made available to the blood need not be ruled out [7], The aim of the present study was not to tackle the complex subject of the mechanism for iron absorption but to estab lish whether riboflavin deficiency might im pair this process. The results show that both iron accumulation in rat pups and iron-mo bilising activity in gastro-intestinal mucosa are severely affected by riboflavin deficiency.…”

Section: Discussionmentioning

confidence: 99%

Investigation into the Relative Effects of Riboflavin Deprivation on Iron Economy in the Weanling Rat and the Adult

Powers¹

1986

Ann Nutr Metab

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Young rapidly-growing weanling rats accumulate ferritin iron in the liver; riboflavin deficiency inhibits this process and is associated with reduced in vitro iron-mobilising activity at the gastro-intestinal mucosa. Adult rats that are not growing tend to maintain existing stores of iron. Whereas riboflavin deficiency reduces in vitro iron-mobilising activity at the gastro-intestinal mucosa, this has no impact on body iron stores in these animals. Levels of circulating iron, on the other hand, are significantly reduced, possibly due to some interference with iron release from the reticuloendothelial system. The magnitude of the impact of riboflavin deficiency on iron mobilisation from body stores and iron absorption may depend upon a number of factors, likely to include the size of existing hepatic iron stores and the demand for rapid iron turnover.

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“…In intestinal cells, as in all cells, ferritin concentrations are regulated by iron dependent control of protein synthesis and degradation [21-23]. Data show that absorbed iron not exported from the enterocyte is stored in ferritin, but the recent awareness that, in solution at least, ferritin protein is a dynamic manager of iron, suggests the possibility of a dynamic role for ferritin during the process of intestinal iron absorption that has been little considered.…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling of the dynamic storage of iron in ferritin

et al. 2010

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BackgroundIron is essential for the maintenance of basic cellular processes. In the regulation of its cellular levels, ferritin acts as the main intracellular iron storage protein. In this work we present a mathematical model for the dynamics of iron storage in ferritin during the process of intestinal iron absorption. A set of differential equations were established considering kinetic expressions for the main reactions and mass balances for ferritin, iron and a discrete population of ferritin species defined by their respective iron content.ResultsSimulation results showing the evolution of ferritin iron content following a pulse of iron were compared with experimental data for ferritin iron distribution obtained with purified ferritin incubated in vitro with different iron levels. Distinctive features observed experimentally were successfully captured by the model, namely the distribution pattern of iron into ferritin protein nanocages with different iron content and the role of ferritin as a controller of the cytosolic labile iron pool (cLIP). Ferritin stabilizes the cLIP for a wide range of total intracellular iron concentrations, but the model predicts an exponential increment of the cLIP at an iron content > 2,500 Fe/ferritin protein cage, when the storage capacity of ferritin is exceeded.ConclusionsThe results presented support the role of ferritin as an iron buffer in a cellular system. Moreover, the model predicts desirable characteristics for a buffer protein such as effective removal of excess iron, which keeps intracellular cLIP levels approximately constant even when large perturbations are introduced, and a freely available source of iron under iron starvation. In addition, the simulated dynamics of the iron removal process are extremely fast, with ferritin acting as a first defense against dangerous iron fluctuations and providing the time required by the cell to activate slower transcriptional regulation mechanisms and adapt to iron stress conditions. In summary, the model captures the complexity of the iron-ferritin equilibrium, and can be used for further theoretical exploration of the role of ferritin in the regulation of intracellular labile iron levels and, in particular, as a relevant regulator of transepithelial iron transport during the process of intestinal iron absorption.

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Ferritin and intestinal iron absorption: pancreatic enzymes and free iron

Cited by 37 publications

References 0 publications

Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium

Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium

Investigation into the Relative Effects of Riboflavin Deprivation on Iron Economy in the Weanling Rat and the Adult

Mathematical modeling of the dynamic storage of iron in ferritin

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