Intestinal iron absorption: current concepts circa 2000

doi:10.1016/S1590-8658(00)80045-6

Digestive and Liver Disease

Volume 32, Issue 1, January–February 2000, Pages 56-61

https://doi.org/10.1016/S1590-8658(00)80045-6 Get rights and content

Abstract

Iron is essential for all mammalian cells, and particularly needed for the production of erythrocyte haemoglobin. However, excess iron is toxic, and tissue iron concentrations must be strictly regulated. This regulation occurs at the sites of entrance of iron into the body: in the placenta before birth, and the small intestine after birth. Although iron homeostasis has been intensively studied for half a century, the molecular details have only recently begun to emerge. This review will cover current information on intestinal iron absorption.

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It additionally contributes towards maintaining redox homeostasis by regulating excessive levels of primary toxicants that are responsible for the generation of reactive oxygen species (ROS), cellular damage and death (Dixon & Stockwell, 2014). An adult human absorbs 1–2 mg iron per day from daily diet for compensation of daily iron loss due to blood loss, epithelial cell shedding in digestive tract and sweating (Andrews, 2000). Iron from the diet is absorbed in two different forms, non-heme iron (organic): present mainly in vegetables/pulses/grains, and heme iron (ferrous iron protoporphyrin IX): present in animal tissue (Johnson-Wimbley & Graham, 2011) (Fig. 1).
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Role of transferrin: An iron-binding protein in health and diseases
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Transferrin (Tf) is a monomeric iron-binding glycoprotein produced largely in the liver. Each mole of Tf is capable of binding to two moles of iron in two homologous iron-binding domains. It is the crucial transport protein that shuttles iron in the blood for most life-sustaining processes. Tf is transported into the cells by binding with the Tf receptor, which acts as a carrier for Tf in maintaining iron homeostasis in cells via receptor-mediated endocytosis. Iron is a vital element for several metabolic pathways and physiological processes. Tf transports iron through the blood to various tissues such as the liver, spleen, and bone marrow. The maintenance of iron homeostasis is essential and insufficient or excess amounts are harmful to the human body. This biomarker gives insight into a patient’s pathology, which is important for treatment. Therefore Tf plays a central role in iron metabolism and is responsible for ferric-ion delivery. Thus Tf or iron-binding protein is an important biomarker for good health, can reveal if someone has functional iron depletion, and can be provided as a supplement.
Classification and structural analyses of mutational landscapes in hemochromatosis factor E protein: A protein defective in the hereditary hemochromatosis
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Citation Excerpt :
The hereditary hemochromatosis (HH) or iron overloading is attributed to the erroneous regulation of iron homeostasis inside the body (Andrews, 2000b; Bacon, 1996; Kell, 2009). This unusual increase in the iron levels is caused by elevated iron absorption from the small intestine and progressive deposition in vital organs including liver (Andrews, 2000a). The initial infection leads to the development of cirrhosis conditions in the liver results in the development of hepatocellular carcinoma (Fleming and Sly, 2002; Lv et al., 2016a).
Hereditary hemochromatosis (HH) is a recessive disease, associated with an elevated level of iron in the parenchymal cells of primary organs. The isolates from infected individuals showed a high frequency of p.Cys282Tyr and p.His63Asp substitutions in human hemochromatosis protein (HFE). Here, we have utilized several advanced computational tools to see the impact of experimentally reported mutations in the HFE gene on the structure, function and stability of HFE protein which is directly associated with the HH. Changes in the conformational behavior between the native HFE and its mutants were further analyzed by molecular dynamics simulations in the explicit solvent conditions. We extensively analyzed p.Cys282Tyr mutation which is predicted as a destabilizing and is primarily associated with the HH. The highest destabilizing effects were observed in p.Val53Met and p.Val59Met but were predicted to be a non-disease associated mutations. We further observed that, p.Val59Met mutation is associated with the aggregation and thus causing HH. We further predicted 56 disease causing mutations which presumably affects the structure, function, and stability of HFE protein. The structural insights into these predicted mutations may provide a newer insight into the understanding the mechanism of HH and its therapeutic strategies.
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Copper is a trace element, important for the function of many cellular enzymes. Copper ions can adopt distinct redox states oxidized Cu(II) or reduced (I), allowing the metal to play a pivotal role in cell physiology as a catalytic cofactor in the redox chemistry of enzymes, mitochondrial respiration, iron absorption, free radical scavenging and elastin cross-linking. If present in excess, free copper ions can cause damage to cellular components and a delicate balance between the uptake and efflux of copper ions determines the amount of cellular copper. In biological systems, copper homeostasis has been characterized at the molecular level. It is coordinated by several proteins such as glutathione, metallothionein, Cu-transporting P-type ATPases, Menkes and Wilson proteins and by cytoplasmic transport proteins called copper chaperones to ensure that it is delivered to specific subcellular compartments and thereby to copper-requiring proteins.
Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes
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Using the Xenopus oocyte expression system, human Nramp2, a human intestinal iron transporter, was shown to work as a cadmium transporter. An 1824-bp human Nramp2 cDNA was constructed by PCR cloning from reverse transcription products of human kidney mRNA. When the pH of the extracellular solution was 6.0, human Nramp2 transported ¹⁰⁹Cd²⁺. Substitution of external Cl⁻ with NO3− had no effect on human Nramp2-dependent cadmium uptake. The concentration-dependent Cd²⁺ transport of human Nramp2 indicated Michaelis–Menten type transport with an average K_m value of 1.04 ± 0.13 μM and an average V_max of 14.7 ± 1.9 pmol/oocyte/h (n = 3). Cd²⁺ transport via human Nramp2 was inhibited significantly by Cd²⁺, Fe²⁺, Pb²⁺, Mn²⁺, Cu²⁺, and Ni²⁺, while it was not inhibited by Hg²⁺ and Zn²⁺. Transport of 0.1 μM Cd²⁺ by human Nramp2 was inhibited by metallothionein (IC50 = 0.14 μM). Therefore, human Nramp2 is suggested to function as a pH-dependent cadmium absorption transporter on the luminal membrane of human intestinal cells.
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Intestinal iron absorption: current concepts circa 2000

Abstract

Blood

Cell

Blood

Blood

Blood

Blood

Blood

Cell

Gastroenterology

Iron and heme: crucial carriers and catalysts

Prevalence of iron deficiency in the United States

J Am Med Assn

Bioavailability of dietary iron in man

Annu Rev Nutr

Iron absorption

Annu Rev Med

Regional specificity of iron uptake by small intestinal brush-border membranes from normal and iron-deficient mice

Am J Physiol

Characterization and partial purification of a ferrireductase from human duodenal microvillus membranes

Biochem J

The behavior and stability of ironascorbate complexes in solution

J Food Sci

Iron speciation at physiological pH in media containing ascorbate and oxygen

Br J Nutr

Defect of intestinal mucosal iron uptake in mice with hereditary microcytic anemia

Active transport of iron by intestine: selective genetic defect in the mouse

Nature

Hereditary defect of intestinal iron transport in mice with sex-linked anemia

J Clin Invest

Ferritin distribution and synthesis in sex-linked anemia

J Lab Clin Med

Microcytic anemia mice have a mutation in Nramp2, a candidate iron transporter gene

Nat Genet