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Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload
Andrew J. Schwartz, … , Justin A. Colacino, Yatrik M. Shah
Andrew J. Schwartz, … , Justin A. Colacino, Yatrik M. Shah
Published October 23, 2018
Citation Information: J Clin Invest. 2019;129(1):336-348. https://doi.org/10.1172/JCI122359.
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Research Article Gastroenterology

Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload

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Abstract

Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin, a liver-derived hormone that controls iron mobilization through its molecular target ferroportin (FPN), the only known mammalian iron exporter. This pathway is perturbed in diseases that cause iron overload. Additionally, intestinal HIF-2α is essential for the local absorptive response to systemic iron deficiency and iron overload. Our data demonstrate a hetero-tissue crosstalk mechanism, whereby hepatic hepcidin regulated intestinal HIF-2α in iron deficiency, anemia, and iron overload. We show that FPN controlled cell-autonomous iron efflux to stabilize and activate HIF-2α by regulating the activity of iron-dependent intestinal prolyl hydroxylase domain enzymes. Pharmacological blockade of HIF-2α using a clinically relevant and highly specific inhibitor successfully treated iron overload in a mouse model. These findings demonstrate a molecular link between hepatic hepcidin and intestinal HIF-2α that controls physiological iron uptake and drives iron hyperabsorption during iron overload.

Authors

Andrew J. Schwartz, Nupur K. Das, Sadeesh K. Ramakrishnan, Chesta Jain, Mladen T. Jurkovic, Jun Wu, Elizabeta Nemeth, Samira Lakhal-Littleton, Justin A. Colacino, Yatrik M. Shah

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Figure 1

Temporal disruption of hepatic hepcidin activates intestinal HIF-2α and leads to rapid iron accumulation.

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Temporal disruption of hepatic hepcidin activates intestinal HIF-2α and ...
(A) Schematic representation of mice with temporal disruption of hepatocyte hepcidin. (B) qPCR analysis of hepatic hepcidin (Hamp) transcript expression levels (n = 3–8 per group). (C) Representative Prussian blue iron staining and H&E staining of liver tissue from HampΔLiv mice. Original magnification, ×20 (n = 3 per group). (D–F) Serum (D), heart (E), and pancreatic iron content (F) (n = 3–14 per group). (G) Representative HIF-2α staining of duodenal sections 2 weeks after tamoxifen injection into Hampfl/fl and HampΔLiv mice. Original magnification, ×20 (n = 3 per group). (H) Western blot analysis of FPN, DMT1, DCYTB, and TFR1 expression in duodenal membrane fractions (n = 2–3 per group). (I) qPCR antalysis of duodenal HIF-2α–specific and iron-handling transcripts 2 weeks after tamoxifen injection into Hampfl/fl and HampΔLiv mice (n = 5–8 per group). Data represent the mean ± SEM. Male samples are designated as squares, and female samples are designated as circles. Significance was determined by 1-way ANOVA with Tukey’s post hoc test (B and D–F) or 2-tailed, unpaired t test (I). *P < 0.05, ***P < 0.001, and ****P < 0.0001 versus the Hampfl/fl group.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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