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J Clin Invest. 2019 Jan 2;129(1):336-348. doi: 10.1172/JCI122359. Epub 2018 Dec 10.

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

Author information

1
Department of Molecular and Integrative Physiology, and.
2
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
3
Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
4
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
5
Environmental Health Sciences.
6
Nutritional Sciences, and.
7
Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.

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.

KEYWORDS:

Gastroenterology; hypoxia

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