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

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 5

The intestinal transcriptome during systemic iron deficiency resembles that of hepcidin deficiency–mediated iron overload.

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The intestinal transcriptome during systemic iron deficiency resembles t...
(A) Experimental design for the samples used in whole-genome RNA-Seq. (B) qPCR analysis of liver Hamp transcript levels in mice on an iron-replete (IR) or low-iron (LI) diet (n = 8–9 per group). (C) Dendrogram comparing genotype-diet interactions following unsupervised hierarchical clustering of genes differentially expressed at a high-stringency FDR of less than 0.01 (n = 3 per group). (D) Heatmap of genes used for unsupervised hierarchical clustering (n = 3 per group). (E) Lower-stringency differential expression analysis at a FDR of less than 0.1 to uncover transcripts in the RNA-Seq data set unique to iron deficiency and hepcidin deficiency. Genes highlighted in red are novel intestinal transcripts regulated by both low iron and hepcidin deficiency (n = 3 per group). Male samples are designated as squares, and female samples are designated as circles. FC, fold change. Data represent the mean ± SEM. Statistical significance was determined by 2-way ANOVA with Tukey’s post hoc test. ****P < 0.0001 versus iron-replete Hampfl/fl.