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Research Article

The Regulation of Cellular Iron Metabolism

, , &
Pages 413-459 | Published online: 10 Oct 2008
 

Abstract

While iron is an essential trace element required by nearly all living organisms, deficiencies or excesses can lead to pathological conditions such as iron deficiency anemia or hemochromatosis, respectively. A decade has passed since the discovery of the hemochromatosis gene, HFE, and our understanding of hereditary hemochromatosis (HH) and iron metabolism in health and a variety of diseases has progressed considerably. Although HFE-related hemochromatosis is the most widespread, other forms of HH have subsequently been identified. These forms are not attributed to mutations in the HFE gene but rather to mutations in genes involved in the transport, storage, and regulation of iron. This review is an overview of cellular iron metabolism and regulation, describing the function of key proteins involved in these processes, with particular emphasis on the liver's role in iron homeostasis, as it is the main target of iron deposition in pathological iron overload. Current knowledge on their roles in maintaining iron homeostasis and how their dysregulation leads to the pathogenesis of HH are discussed.

Abbreviations and Glossary
=

Note that proteins are abbreviated in regular font and their genes in italics, using upper case for both. We have chosen not to distinguish human (upper case) from animal (lower case) proteins and genes, as many statements and citations refer to both categories.

β2M,=

β2-microglobulin;

BMP,=

bone morphogenetic protein;

BMPR,=

bone morphogenetic protein receptor;

Caco-2,=

human colorectal adenocarcinoma cell line;

CHO,=

Chinese hamster ovary cell line;

CP,=

ceruloplasmin;

DCYTB,=

duodenal cytochrome b;

DMT1,=

divalent metal transporter 1;

ERK,=

extracellular signal-regulated kinase;

FLVCR,=

feline leukemic virus subgroup C receptor;

FPN,=

ferroportin, iron exporter;

HAMP,=

hepcidin anti-microbial peptide;

HCP1,=

heme carrier protein 1;

HEK293,=

human embryonic kidney epithelial cell line;

HeLa cells,=

cervical cancer cells taken from Henrietta Lacks;

Hep3B,=

human hepatocellular carcinoma cell line;

HepG2,=

human hepatoblastoma cell line;

HFE,=

hemochromatosis protein;

HH,=

hereditary hemochromatosis;

HIF-1,=

hypoxia-inducible factor-1;

HJV,=

hemojuvelin;

HuH7,=

human hepatocellular carcinoma cell line;

IFN-γ,=

interferon-gamma;

IL,=

interleukin;

IRE,=

iron responsive element;

IREG1,=

iron-regulated transporter 1;

IRP,=

iron regulatory protein;

K562,=

human erythroleukemic cell line;

LPS,=

lipopolysaccharide;

MAPK,=

mitogen-activated protein kinase;

MTP1,=

metal transport protein 1;

NTBI,=

non-transferrin-bound iron;

RGM,=

repulsive guidance molecule;

SMAD,=

the name for the family of SMAD proteins that are homologs of both the drosophila protein, mothers against decapentaplegic (MAD), and the Caenorhabditis elegans protein SMA, with the name being a combination of the two. In Drosophila research, a mutation in the MAD gene in the mother was found to repress the decapentaplegic gene in the embryo (The Free Dictionary by Farlex);

STAT3,=

signal transducer and activator of transcription 3;

STEAP3,=

six-transmembrane epithelial antigen of prostate protein 3;

TBI,=

transferrin-bound iron;

Tf,=

transferrin;

TFR1,=

transferrin receptor 1;

TFR2,=

transferrin receptor 2;

UTR,=

untranslated region;

ZIP14,=

Zrt- Irt-like protein 14.

Abbreviations and Glossary
=

Note that proteins are abbreviated in regular font and their genes in italics, using upper case for both. We have chosen not to distinguish human (upper case) from animal (lower case) proteins and genes, as many statements and citations refer to both categories.

β2M,=

β2-microglobulin;

BMP,=

bone morphogenetic protein;

BMPR,=

bone morphogenetic protein receptor;

Caco-2,=

human colorectal adenocarcinoma cell line;

CHO,=

Chinese hamster ovary cell line;

CP,=

ceruloplasmin;

DCYTB,=

duodenal cytochrome b;

DMT1,=

divalent metal transporter 1;

ERK,=

extracellular signal-regulated kinase;

FLVCR,=

feline leukemic virus subgroup C receptor;

FPN,=

ferroportin, iron exporter;

HAMP,=

hepcidin anti-microbial peptide;

HCP1,=

heme carrier protein 1;

HEK293,=

human embryonic kidney epithelial cell line;

HeLa cells,=

cervical cancer cells taken from Henrietta Lacks;

Hep3B,=

human hepatocellular carcinoma cell line;

HepG2,=

human hepatoblastoma cell line;

HFE,=

hemochromatosis protein;

HH,=

hereditary hemochromatosis;

HIF-1,=

hypoxia-inducible factor-1;

HJV,=

hemojuvelin;

HuH7,=

human hepatocellular carcinoma cell line;

IFN-γ,=

interferon-gamma;

IL,=

interleukin;

IRE,=

iron responsive element;

IREG1,=

iron-regulated transporter 1;

IRP,=

iron regulatory protein;

K562,=

human erythroleukemic cell line;

LPS,=

lipopolysaccharide;

MAPK,=

mitogen-activated protein kinase;

MTP1,=

metal transport protein 1;

NTBI,=

non-transferrin-bound iron;

RGM,=

repulsive guidance molecule;

SMAD,=

the name for the family of SMAD proteins that are homologs of both the drosophila protein, mothers against decapentaplegic (MAD), and the Caenorhabditis elegans protein SMA, with the name being a combination of the two. In Drosophila research, a mutation in the MAD gene in the mother was found to repress the decapentaplegic gene in the embryo (The Free Dictionary by Farlex);

STAT3,=

signal transducer and activator of transcription 3;

STEAP3,=

six-transmembrane epithelial antigen of prostate protein 3;

TBI,=

transferrin-bound iron;

Tf,=

transferrin;

TFR1,=

transferrin receptor 1;

TFR2,=

transferrin receptor 2;

UTR,=

untranslated region;

ZIP14,=

Zrt- Irt-like protein 14.

Notes

* Editor's note: Hepcidin refers to the protein and HAMP is the nomenclature for the gene.

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