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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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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Figure 1

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Hjv expression in periportal hepatocytes. (A) Targeting strategy used f...
Hjv expression in periportal hepatocytes. (A) Targeting strategy used for homologous recombination in ES cells to eliminate Hjv gene function. The Hjv locus contains 3 coding exons (yellow). A targeting construct containing eGFP (dark gray) followed by IRES-NLS-lacZ-pA (blue) and thymidine kinase neomycin (TK-neo) (light gray) cassettes was integrated in frame into the second coding exon of Hjv. The probe used for genomic Southern blot analysis is indicated in blue. Integrated cassette is not drawn to scale. STOP, carboxyterminal stop codon. (B) Genomic Southern blot of Hjv+/+, Hjv+/–, and Hjv–/– genomic DNA using the probe indicated in A. (C) Northern blot analysis of total RNA isolated from P21 hindlimb muscles of Hjv+/+ and Hjv–/– mice probed for the expression of Hjv (top) and GAPDH (bottom). (D) Schematic drawing depicting the territories of liver lobules. Portal tracts (PT) are indicated in blue; central veins (CVs) are shown in red. Note that solid lines in D–G outline the hexagonally shaped hepatic lobule with PTs at the corners. (E–G) Detection of enzymatic lacZ activity in liver from 3-month-old Hjv+/– mice analyzed on vibratome (E) or cryostat (F and G) sections. Red circles indicate CV, blue circles indicate PT. Inset in (G) depicts high magnification of individual binuclear hepatocytes that express lacZ. (H–K) Immunohistochemical detection of HNF4α (H, J, and K: red), lacZ (I, J, and K: green), and SYTOX green (nuclei; K: blue) in liver from 3-month-old Hjv+/– mice. Arrows point to binuclear Hjv-expressing hepatocytes. Scale bar: 530 μm (E); 260 μm (F); 70 μm (G); 30 μm (inset in G); 40 μm (H–K)