# Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $632,135

## Abstract

SUMMARY
Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism. Iron is an essential trace mineral,
involved in many vital cellular and organismal functions. Organismal iron content is controlled by dietary
absorption, iron partitioning in erythrocytes, iron recycling by macrophages and iron storage in hepatocytes.
The hormone, hepcidin is a master regulator of systemic iron content as it negatively regulates ferroportin, the
primary cellular iron exporter mediating iron flow from enterocytes, macrophages and hepatocytes into the
circulation. We have shown that heparan sulfate is key component of hepcidin regulation. Inhibition of heparan
sulfate biosynthesis in hepatoma cells and in mice reduces baseline, BMP6-stimulated, and IL6-stimulated
hepcidin expression and worsens the pathophysiology characteristic of anemia of inflammation. We have now
identified syndecan-1 as the primary HSPG regulating liver hepcidin expression based on genetic and
pharmacological inactivation of syndecan-1 expression in human and mouse hepatoma cells. Our findings
imply that endogenous hepatic syndecan-1 serves as a template to support signaling complexes regulating
hepcidin expression and iron metabolism. We propose to extend our studies to human hepatocytes; to
determine the mechanism underlying the requirement for Sdc1-mediated regulation of hepcidin
expression; and to exploit this information to develop strategies to treat disorders characterized by
iron overloading. To achieve these goals, we will (i) Examine the role of syndecan-1 in driving basal and iron-
inducible hepcidin expression in human hepatocytes; (ii) Determine the mechanism of syndecan-1 regulation of
hepcidin expression and (iii) Evaluate the efficacy of genetic and pharmacological syndecan-1 targeting to
correct iron dyshomeostasis in iron-loading disease models. The overarching goal of this proposal is to
evaluate the relationship of syndecan-1 structure to iron metabolism, with the long-range goal of defining new
potential targets to reduce the risk of iron-loading disorders, such as anemia of inflammation.

## Key facts

- **NIH application ID:** 10099666
- **Project number:** 1R01DK126848-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Philip Gordts
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $632,135
- **Award type:** 1
- **Project period:** 2021-02-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099666

## Citation

> US National Institutes of Health, RePORTER application 10099666, Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism (1R01DK126848-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10099666. Licensed CC0.

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