# Zip Proteins and Iron Metabolism

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $392,335

## Abstract

PROJECT SUMMARY/ABSTRACT
The iron overload disorder hereditary hemochromatosis is an endocrine liver disease that results from an inability
to produce sufficient amounts of hepcidin, the iron-regulatory hormone produced by the liver. In
hemochromatosis, increased absorption of dietary iron leads to the appearance of plasma non-transferrin-bound
iron (NTBI), which is taken up by various tissues and cells leading to tissue iron overload and related pathology.
Plasma NTBI is also commonly seen in the hematologic disease thalassemia major, an inherited blood disorder
that requires regular blood transfusions, which over time result in iron overload. Although NTBI is the major
contributor to tissue iron loading, our understanding of the molecular mechanisms that mediate NTBI uptake is
incomplete. The primary long-term objective of this proposal is to define the proteins that transport iron into
various tissues and cells, particularly those affected by iron-overload related pathology. Our central hypothesis
is that the membrane transport proteins ZIP14 and ZIP8 participate in iron homeostasis and NTBI uptake. In the
previous funding period we found that ZIP14 is the primary NTBI uptake mechanism in hepatocytes and
pancreatic acinar cells, and that ZIP14 is required for iron loading of the liver and pancreas in mouse models of
hemochromatosis and dietary iron overload. We also generated a variety of conditional Zip8 knockout mouse
models to interrogate the roles of ZIP8 in iron metabolism and iron overload. In Aim 1 of the proposed research,
we will continue to define the roles of ZIP14 in tissue iron loading by using ZIP14 knockout (Zip14-/-) mice
intercrossed with hemojuvelin knockout (Hjv-/-) mice, a model of juvenile hemochromatosis. The current focus
will be on endocrine organs including the anterior pituitary gland and adrenal gland. Using Hjv-/- mice, we will
also assess the efficacy of reducing ZIP14 expression (pharmacologically or genetically) combined with iron
chelation in mitigating tissue iron overload. In Aim 2, we will determine how ZIP14-mediated iron loading of
pancreatic beta cells leads to beta cell dysfunction and diabetes. For this aim we generated a transgenic mouse
model that overexpresses ZIP14 specifically in beta cells. When loaded with iron, the ZIP14 transgenic mice,
similar to iron-loaded humans, accumulate iron in beta cells and develop diabetes. We will characterize the
development of diabetes in these mice, focusing on changes that occur in beta cells. In Aim 3, we will continue
to define the roles of ZIP8 in iron homeostasis, particularly its apparent role in stress erythropoiesis. To define
the roles of ZIP8 in tissue iron loading, we will utilize inducible Zip8-/- mice as well as Zip8-/-;Zip14-/- double
knockout mice, which will help to determine whether these two homologous proteins can compensate for each
other.

## Key facts

- **NIH application ID:** 10145659
- **Project number:** 5R01DK080706-13
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Mitchell D Knutson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,335
- **Award type:** 5
- **Project period:** 2009-09-17 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145659

## Citation

> US National Institutes of Health, RePORTER application 10145659, Zip Proteins and Iron Metabolism (5R01DK080706-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10145659. Licensed CC0.

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