Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload
Vera Niederkofler, … , Rishard Salie, Silvia Arber
Vera Niederkofler, … , Rishard Salie, Silvia Arber
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2180-2186. https://doi.org/10.1172/JCI25683.
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Research Article Genetics

Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload

Abstract

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.

Authors

Vera Niederkofler, Rishard Salie, Silvia Arber

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Iron accumulation in Hjv-mutant mice. (A–H) Histological detection of ir...
Iron accumulation in Hjv-mutant mice. (A–H) Histological detection of iron content on cryostat sections of liver (A–D) and spleen (E–H) of wild-type (A, C, E, and G) and Hjv–/– (B, D, F, and H) mice. Note uniform iron accumulation in the liver of 2.5-month-old Hjv-mutant mice and absence thereof in the red pulp of the spleen. (I) Quantitative determination of iron content (μmol/g dry weight) in various organs of 2.5-month-old wild-type (white), Hjv+/– (gray), and Hjv–/– (black) mice (n = 5 for each group). Asterisks indicate significant changes (P < 0.05) in Hjv–/– mice as compared with wild-type littermates. (J) Time course (P12–P300) of iron content (μmol/g dry weight) determined in Hjv–/– mice (squares) compared with pooled wild-type and Hjv+/– mice (triangles). Liver (green) and spleen (blue) are depicted in the graph. At least 3 animals per time point and genotype were included in the analysis. Asterisks indicate significant changes (P < 0.05) in Hjv–/– mice as compared with pooled wild-type and Hjv+/– littermates. Scale bar: 270 μm (A and B); 45 μm (C and D); 1.2 mm (E and F); 100 μm (G and H).