# Mechanisms of Heme and Non-heme Iron Absorption in Murine Models of Iron Overload

> **NIH NIH R56** · UNIVERSITY OF FLORIDA · 2022 · $100,000

## Abstract

Project Summary
Iron is an essential nutrient for rats, mice, and humans, yet iron in excess is toxic. Iron deficiency (ID) and iron
overload (IO) thus result in severe homeostatic perturbations. Since iron excretion is inefficient and unregulated,
intestinal iron absorption dictates overall body iron levels. Dietary iron exists mainly as non-heme and heme iron,
and both contribute significantly to iron nutriture. Non-heme iron absorption by duodenal enterocytes critically
relies on the iron importer divalent metal-ion transporter 1 (DMT1) and the iron exporter ferroportin (FPN).
Mechanisms of heme-iron absorption have not been clarified. Inappropriately elevated absorption of heme and
non-heme iron underlies iron loading in the genetic disorders hereditary hemochromatosis (HH) and β-
thalassemia (βthal). Iron overload can cause liver disease, arthropathies, osteoporosis, cardiomyopathy,
diabetes mellitus and impotence. HH is caused by mutations in genes that regulate transcription of the Hamp
gene in hepatocytes. Hamp encodes the iron-regulatory hormone hepcidin, which regulates serum iron content
by modulating FPN levels in duodenal enterocytes and reticuloendothelial macrophages (which store iron). The
most common gene mutated in HH is homeostatic iron regulator (HFE). In the U.S., ~1:300 adults of Northern
European descent is homozygous for HFE mutations1, significantly increasing risk for severe liver disease2. HH
can also be caused by mutations in Hamp which impair production of the functional hormone. βthal is an iron-
loading anemia, typified by ineffective erythropoiesis, due to β-globin gene mutations, and disordered iron
metabolism. Elevated iron absorption (due to low hepcidin) and frequent blood transfusion both contribute to iron
loading. In a transfusion-independent form of the disease, βthal intermedia (βTI), excessive iron absorption is
the main contributor to iron loading. In HH and βTI, increased FPN activity (due to low hepcidin) depletes
intracellular iron from duodenal enterocytes, which upregulates DMT1. The mechanism of DMT1 induction
involves a transcript variant that contains an iron-responsive element (+IRE) in the 3’ UTR. When iron is low, this
+IRE variant is stabilized by binding of an iron-regulatory protein (IRP) to the IRE motif thus stabilizing the
transcript and increasing translation. High DMT1 and FPN thus precipitate excessive iron absorption. In Aim 1,
we seek to mitigate iron loading in Hamp KO and Th3/+ mice by targeting the +IRE DMT1 mRNA using our Folic
Acid-coupled Ginger Nanoparticle-derived Lipid Vector (FA-GDLV) siRNA delivery system. We further seek to
ascertain if non-heme and heme-iron absorption are coordinately regulated to maintain iron homeostasis under
physiological conditions and to clarify whether this regulation goes awry in ID and IO (in Aim 2). Additional
experimentation will elucidate whether DMT1 and FPN modulate heme-iron absorption and contribute to iron
loading in HH (in Aim 3). Amb...

## Key facts

- **NIH application ID:** 10701227
- **Project number:** 1R56DK134583-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** James F. Collins
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $100,000
- **Award type:** 1
- **Project period:** 2022-09-25 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701227

## Citation

> US National Institutes of Health, RePORTER application 10701227, Mechanisms of Heme and Non-heme Iron Absorption in Murine Models of Iron Overload (1R56DK134583-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10701227. Licensed CC0.

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