Niederkofler, V. , Salie, R. & Arber, S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J. Clin. Invest. 115, 2180-2186

Biozentrum, Department of Cell Biology, University of Basel, and Friedrich Miescher Institute, Basel, Switzerland.
Journal of Clinical Investigation (Impact Factor: 13.22). 09/2005; 115(8):2180-6. DOI: 10.1172/JCI25683
Source: PubMed


Iron homeostasis plays a critical role in many physiological processes, notably synthesis of heme proteins. Dietary iron sensing and inflammation converge in the control of iron absorption and retention by regulating the expression of hepcidin, a regulator of the iron exporter ferroportin. Human mutations in the glycosylphosphatidylinositol-anchored protein hemojuvelin (HJV; also known as RGMc and HFE2) cause juvenile hemochromatosis, a severe iron overload disease, but the way in which HJV intersects with the iron regulatory network has been unclear. Here we show that, within the liver, mouse Hjv is selectively expressed by periportal hepatocytes and also that Hjv-mutant mice exhibit iron overload as well as a dramatic decrease in hepcidin expression. Our findings define a key role for Hjv in dietary iron sensing and also reveal that cytokine-induced inflammation regulates hepcidin expression through an Hjv-independent pathway.

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Available from: Vera Niederkofler, Oct 14, 2015
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    • "These results indicate that if the substrate of matriptase-2 is downstream of hemojuvelin, it is likely to be along the SMAD signaling pathway. It is known that inflammatory cytokines, such as LPS and IL6, can induce Hamp expression in the absence of Hjv (Niederkofler et al., 2005), presumably via the Stat3 and Stat5 pathways (Verga Falzacappa et al., 2007; Meynard et al., 2013). However, it was surprising to find that the lack of both Hjv and Tmprss6 in mice did not impair the responsiveness of hepcidin to BMP2 and IL6, but did fail to respond to iron challenge (Truksa et al., 2009). "
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    ABSTRACT: Matriptase-2, encoded by the TMPRSS6 gene, is a member of the type II transmembrane serine protease family. Matriptase-2 has structural and enzymatic similarities to matriptase-1, which has been implicated in cancer progression. Matriptase-2 was later established to be essential in iron homeostasis based on the phenotypes of iron-refractory iron deficiency anemia identified in mouse models as well as in human patients with TMPRSS6 mutations. TMPRSS6 is expressed mainly in the liver and negatively regulates the production of hepcidin, the systemic iron regulatory hormone. This review focuses on the current understanding of matriptase-2 biochemistry, and its role in iron metabolism and cancer progression. In light of recent investigations, the function of matriptase-2 in hepcidin regulation, how it is being regulated, as well as the therapeutic potential of matriptase-2 are also discussed.
    Frontiers in Pharmacology 05/2014; 5:114. DOI:10.3389/fphar.2014.00114 · 3.80 Impact Factor
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    • "In addition to the liver, HJV mRNA is also highly expressed in skeletal muscle and heart (Niederkofler et al., 2004; Papanikolaou et al., 2004), and has been detected in other tissues (Rodriguez Martinez et al., 2004, Rodriguez et al., 2007; Gnana-Prakasam et al., 2009; Luciani et al., 2011). Tissue specific differences in HJV mRNA regulation and HJV protein glycosylation patterns have also been described (Niederkofler et al., 2005; Fujikura et al., 2011). It was previously hypothesized that skeletal muscle and/or heart could serve as a source of sHJV to suppress hepcidin synthesis in response to iron deficiency or hypoxia (Lin et al., 2005; Zhang et al., 2005). "
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    ABSTRACT: Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
    Frontiers in Pharmacology 05/2014; 5:104. DOI:10.3389/fphar.2014.00104 · 3.80 Impact Factor
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    • "By studying the naturally occurring mutations in humans and using transgenic mouse models, valuable information has been obtained regarding the key molecules involved in the regulation of hepcidin expression by circulating iron and hepatic stored iron. These molecules include HFE (HLA2-linked hemochromatosis gene) [66,67], transferrin receptor 2 (TfR2) [68-70], hemojuvelin (HJV) [71] and bone morphogenetic protein (BMP) [72]. A possible model on the regulation of hepcidin by iron is proposed based on these results (Figure 2). "
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    ABSTRACT: Iron is an important mineral element used by the body in a variety of metabolic and physiologic processes. These processes are highly active when the body is undergoing physical exercises. Prevalence of exercise-induced iron deficiency anemia (also known as sports anemia) is notably high in athletic populations, particularly those with heavy training loads. The pathogenesis of sports anemia is closely related to disorders of iron metabolism, and a more comprehensive understanding of the mechanism of iron metabolism in the course of physical exercises could expand ways of treatment and prevention of sports anemia. In recent years, there have been remarkable research advances regarding the molecular mechanisms underlying changes of iron metabolism in response to physical exercises. This review has covered these advances, including effects of exercise on duodenum iron absorption, serum iron status, iron distribution in organs, erythropoiesis, and hepcidin's function and its regulation. New methods for the treatment of exercise-induced iron deficiency are also discussed.
    Cell and Bioscience 04/2014; 4(1):19. DOI:10.1186/2045-3701-4-19 · 3.63 Impact Factor
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