# Control of iron absorption by intestinal HIF2 in iron and hematological disorders

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $335,630

## Abstract

ABSTRACT
Dysregulation of intestinal iron absorption is a primary feature in iron overload disorders. Hypoxia-inducible
factor 2α (HIF2α) is a critical regulator of iron absorption during increased systemic iron demands (i.e. iron
deficiency, erythropoiesis, and pregnancy). HIF2α regulates expression of the apical iron transport machinery,
divalent metal transporter 1 (DMT-1) and duodenal cytochrome b (Dcytb), and regulates the basolateral iron
exporter ferroportin independent of hepcidin, the master systemic regulator of iron homeostasis. Disrupting
intestinal HIF2α decreases tissue iron accumulation in iron overload disorders, such as β-thalassemia and
heredity hemochromatosis. Moreover, in β-thalassemia, disruption of intestinal HIF2α also improves anemia.
This has laid the foundation for HIF2α-based therapeutics for β-thalassemia and heredity hemochromatosis,
an area actively being researched by Peloton Therapeutics. Although our results demonstrate a central role for
HIF2α in intestinal iron absorption, the underlying mechanisms behind its overlapping and distinct roles in iron
deficiency, β-thalassemia, and heredity hemochromatosis are still unclear. We hypothesize that a decrease
in systemic hepcidin triggers HIF2α activation in intestinal epithelia, leading to an iron-absorptive
response, which is critical for tissue iron accumulation in iron overload disorders. Our long-term goals
are to improve existing HIF2α-based therapies and identify novel HIF2α-based therapies in iron-related
disorders. The major goal of this proposal is to assess the precise mechanisms by which HIF2α selectively
regulates iron absorption and determine if inhibition of HIF2α signaling and downstream mediators can be
used to restrict tissue iron overload. We will pursue our objectives through three interconnected Specific Aims.
Aim 1 will identify mechanisms leading to rapid activation of HIF2α in hereditary hemochromatosis. Our data
suggest a crosstalk between the systemic iron regulator, hepcidin, and intestinal HIF2α. This concept will be
tested in novel mouse models that allow us to acutely and temporally regulate the hepcidin-ferroportin axis.
Aim 2 will characterize precise mechanisms leading to an iron-absorptive HIFα response. We have identified
mothers against decapentaplegic homolog 3 (SMAD3) as a novel factor that is essential for expression of iron-
absorptive (but not glycolytic, angiogenic, or inflammatory) HIF2α target genes. We will elucidate the specific
role and underlying mechanisms behind SMAD3 regulation of HIF2α signaling. Aim 3 will assess the
requirement for HIF2α-induced intestinal ferritinophagy in systemic iron homeostasis and iron overload
disorders. Nuclear coactivator-4 (NCOA4), the major regulator of ferritinophagy, is directly regulated by HIF2α
and is highly induced in iron deficiency, β-thalassemia, and heredity hemochromatosis. We will examine the
role that autophagic ferritin turnover plays in iron absorption using novel mouse mod...

## Key facts

- **NIH application ID:** 9939509
- **Project number:** 5R01DK095201-09
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** YATRIK M SHAH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,630
- **Award type:** 5
- **Project period:** 2012-04-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939509

## Citation

> US National Institutes of Health, RePORTER application 9939509, Control of iron absorption by intestinal HIF2 in iron and hematological disorders (5R01DK095201-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9939509. Licensed CC0.

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