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Babitt, J.L. et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531-539

Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature Genetics (Impact Factor: 29.35). 06/2006; 38(5):531-9. DOI: 10.1038/ng1777
Source: PubMed

ABSTRACT

Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.

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    • "In addition, increased tissue iron activates the Smad pathway by increasing BMP6 production . By binding BMP receptors in complex with the hemojuvelin protein, BMP6 activates the Smad pathway, leading to increased hepcidin production (Babitt et al., 2006). The expression of iron transporters in the duodenum is also regulated by the transcription factor HIF2a, which binds to hypoxia-responsive elements in the promoters of ferroportin and DMT1 (Mastrogiannaki et al., 2009). "
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    • "Liver hepcidin is regulated primarily by the BMP/SMAD signaling pathway, which is considered the iron-dependent mechanism. Hemojuvelin (HJV) acts as a BMP co-receptors [7] and its activity is modulated by a liver-specific membrane protease, named TMPRSS6 [8]. BMP6 has been identified as the major physiological actor, although other BMPs or members of the TGF beta superfamily can induce hepcidin expression in vitro and in vivo. "
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    ABSTRACT: Hepcidin is a peptide hormone that controls systemic iron availability and is upregulated by iron and inflammation. Heparins have been shown to be efficient hepcidin inhibitors both in vitro and in vivo, even when their anticoagulant activity has been abolished by chemical reactions of oxidation/reduction (glycol-split). We analyzed a modified heparin type, characterized by a high, almost saturated, sulfation degree and low molecular weight. It inhibited hepcidin expression in hepatic HepG2 cells, and when used in mice, it readily suppressed liver hepcidin mRNA and serum hepcidin, with a significant decrease of spleen iron. This occurred also in inflammation-model, LPS-treated animals, and after heparin chronic ten-day treatments. The heparin had low/absent anticoagulant activity, as tested for factor-Xa and -IIA, APTT and anti Xa. It reduced triglyceride levels in the mice. This heparin acts faster and is more potent than the glycol split-heparins, probably because of its smaller molecular weight and higher sulfation degree. This modified heparin has potential applications for the treatment of diseases with high hepcidin levels.
    Full-text · Article · Sep 2014 · Biochemical Pharmacology
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    • "The activated complex, in turn, phosphorylates Smad1,5,8/Smad4 complex, which then translocates to nucleus to modulate gene transcription (Wang et al., 2005; Babitt et al., 2006; Kautz et al., 2008). Hemojuvelin (HJV) acts as a coreceptor and is required to fully activate the BMP signaling ability (Babitt et al., 2006). The expression of BMP6 is proportional to hepatic iron concentrations and consistent with Hamp mRNA expression (Kautz et al., 2008). "
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