Abstract
Hepcidin is a liver-derived hormone with a key role in iron homeostasis. In addition to iron, it is regulated by inflammation and hypoxia, although mechanisms of hypoxic regulation remain unclear. In hepatocytes, hepcidin is induced by bone morphogenetic proteins (BMPs) through a receptor complex requiring hemojuvelin (HJV) as a co-receptor. Type II transmembrane serine proteinase (TMPRSS6) antagonizes hepcidin induction by BMPs by cleaving HJV from the cell membrane. Inactivating mutations in TMPRSS6 lead to elevated hepcidin levels and consequent iron deficiency anemia. Here we demonstrate that TMPRSS6 is up-regulated in hepatic cell lines by hypoxia and by other activators of hypoxia-inducible factor (HIF). We show that TMPRSS6 expression is regulated by both HIF-1α and HIF-2α. This HIF-dependent up-regulation of TMPRSS6 increases membrane HJV shedding and decreases hepcidin promoter responsiveness to BMP signaling in hepatocytes. Our results reveal a potential role for TMPRSS6 in hepcidin regulation by hypoxia and provide a new molecular link between oxygen sensing and iron homeostasis.
MeSH terms
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Anemia, Iron-Deficiency / enzymology
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Anemia, Iron-Deficiency / genetics
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Antimicrobial Cationic Peptides / genetics
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Antimicrobial Cationic Peptides / metabolism
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / metabolism
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Cell Hypoxia / physiology
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Cell Line
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Cell Membrane / enzymology*
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Hemochromatosis Protein
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Hepcidins
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / metabolism
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Homeostasis*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Iron / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mutation
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Oxygen / metabolism
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
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Signal Transduction*
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Up-Regulation / genetics
Substances
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Antimicrobial Cationic Peptides
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Basic Helix-Loop-Helix Transcription Factors
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Bone Morphogenetic Proteins
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HAMP protein, human
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HFE protein, human
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HIF1A protein, human
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Hemochromatosis Protein
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Hepcidins
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Histocompatibility Antigens Class I
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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endothelial PAS domain-containing protein 1
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Iron
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Serine Endopeptidases
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TMPRSS6 protein, human
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Oxygen