Hepatic Iron Metabolism

Anderson, Gregory J.; Frazer, David M.

doi:10.1055/s-2005-923314

Cited by 113 publications

(75 citation statements)

References 117 publications

(187 reference statements)

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“…Parenchymal cells are the most abundant cell type in the liver, and they contribute markedly to the regulation of zinc and iron metabolism (16,17). The molecular mechanisms by which these metals are internalized from blood into hepatocytes are only partially understood, however.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular mechanisms by which these metals are internalized from blood into hepatocytes are only partially understood, however. Hepatocytes can acquire iron from blood through multiple routes (17). Under normal conditions, circulating iron is internalized into hepatocytes mainly by the TfR pathway (17).…”

Section: Discussionmentioning

confidence: 99%

“…Hepatocytes can acquire iron from blood through multiple routes (17). Under normal conditions, circulating iron is internalized into hepatocytes mainly by the TfR pathway (17). The normal range of Tf saturation is 20-50%; however, Tf-binding capacity can be supersaturated during iron-overload conditions such as hereditary hemochromatosis, where plasma NTBI is greatly increased (11,18).…”

Section: Discussionmentioning

confidence: 99%

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Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells

Liuzzi

Aydemir

Nam

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

485

375

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Zip14 is a member of the SLC39A zinc transporter family, which is involved in zinc uptake by cells. Up-regulation of Zip14 by IL-6 appears to contribute to the hepatic zinc accumulation and hypozincemia of inflammation. At least three members of the SLC39A family transport other trace elements, such as iron and manganese, in addition to zinc. We analyzed the capability of Zip14 to mediate non-transferrin-bound iron (NTBI) uptake by overexpressing mouse Zip14 in HEK 293H cells and Sf9 insect cells. Zip14 was found to localize to the plasma membrane, and its overexpression increased the uptake of both 65 Zn and 59 Fe. Addition of bathophenanthroline sulfonate, a cell-impermeant ferrous iron chelator, inhibited Zip14-mediated iron uptake from ferric citrate, suggesting that iron is taken up by HEK cells as Fe 2؉ . Iron uptake by HEK and Sf9 cells expressing Zip14 was inhibited by zinc. Suppression of endogenous Zip14 expression by using Zip14 siRNA reduced the uptake of both iron and zinc by AML12 mouse hepatocytes. Zip14 siRNA treatment also decreased metallothionein mRNA levels, suggesting that compensatory mechanisms were not sufficient to restore intracellular zinc. Collectively, these results indicate that Zip14 can mediate the uptake of zinc and NTBI into cells and that it may play a role in zinc and iron metabolism in hepatocytes, where this transporter is abundantly expressed. Because NTBI is commonly found in plasma of patients with hemochromatosis and transfusional iron overload, Zip14-mediated NTBI uptake may contribute to the hepatic iron loading that characterizes these diseases.hemochromatosis ͉ iron transport ͉ liver ͉ zinc transport ͉ inflammation

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells

Liuzzi

Aydemir

Nam

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

485

375

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“…Iron homeostasis in hepatocytes is a microcosm of what happens in the body as a whole [209]. Most of the mechanisms of cellular iron uptake that have been described are operational in hepatocytes.…”

Section: Hepatocytesmentioning

confidence: 99%

Mammalian iron transport

Anderson

Vulpe

2009

Cell. Mol. Life Sci.

264

265

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Iron is essential for basic cellular processes but is toxic when present in excess. Consequently, iron transport into and out of cells is tightly regulated. Most iron is delivered to cells bound to plasma transferrin via a process that involves transferrin receptor 1, divalent metal-ion transporter 1 and several other proteins. Non-transferrin-bound iron can also be taken up efficiently by cells, although the mechanism is poorly understood. Cells can divest themselves of iron via the iron export protein ferroportin in conjunction with an iron oxidase. The linking of an oxidoreductase to a membrane permease is a common theme in membrane iron transport. At the systemic level, iron transport is regulated by the liver-derived peptide hepcidin which acts on ferroportin to control iron release to the plasma.

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“…The haptoglobin/hemopexin system normally binds extracellular (oxyHb) and heme [2]. However, the protective haptoglobin/hemopexin/Albumin/heme oxygenase (HO) systems can be overwhelmed in disease states, including hemolysis and inflammation, resulting in increased circulating levels of free Hb and free (or LDL bound) heme that can attack the endothelium and effect perfusion [6,43,69,70,81,97].…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Perry

Gearhart

Wiener

et al. 2008

Neurobiology of Aging

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From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to Aβ1-42. We showed the oxidized form 1 These authors are co-corresponding authors for all stages of refereeing and publication and contributed equally to this work. Rodney T. Perry; Rm. 210H, 1665 University Blvd.; University of Alabama at Birmingham, Birmingham, USA; Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure Statement:I so state for myself and on behalf of the other authors on the manuscript, Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease, that we have no conflicts and sources of funding that influence the results of this paper, the data is not published or submitted elsewhere, and that appropriate approval and procedures were used concerning human subjects. I also verify that all authors on this manuscript have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of adult Hb (metHb A) binds with greater affinity to Aβ1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C→T) at −158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with Aβ and may protect against the development of AD.

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Hepatic Iron Metabolism

Cited by 113 publications

References 117 publications

Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells

Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells

Mammalian iron transport

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

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