# HSPG Interactions in Liver Disease

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $433,035

## Abstract

ABSTRACT
 The central goal of this R01 proposal is to understand how molecular and cellular interactions of heparan
sulfate proteoglycans (HSPGs) modulate the pathogenesis of acetaminophen (APAP)-induced liver injury
(AILI). Accidental or intentional misuse of APAP is the leading cause of acute liver failure in the Western world.
While mechanisms that trigger AILI are well known, those that facilitate liver recovery are less understood.
HSPGs bind and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the
significance and mechanisms of HSPGs in tissue injury and repair in vivo remain largely unknown. We
examined the role of syndecan-1 (Sdc1), the major cell surface HSPG of hepatocytes, in AILI. Deletion of Sdc1
in mice led to unopposed progression of liver injury in APAP liver disease. However, direct APAP hepatoxicity
at early times after APAP overdose was unaffected by Sdc1 deletion, suggesting that Sdc1 regulates later
mechanisms that affect the progression and outcome of APAP liver disease. The exuberant AILI phenotypes of
Sdc1 null (Sdc1-/-) mice were traced to an exaggerated innate immune response in the liver and a deficiency
in pro-survival Akt signaling in hepatocytes and hepatocyte proliferation, which led to amplification of liver
damage. Administration of purified Sdc1 or heparan compounds containing 2-O-sulfate motifs rescued Sdc1-/-
mice from AILI by inhibiting innate immune responses, and by potentiating hepatocyte proliferation and liver
repair. Furthermore, HS showed a significantly prolonged therapeutic efficacy as compared to N-acetylcysteine
(NAC), the clinical antidote for APAP overdose. These findings suggest that Sdc1 and HS, either alone or in
combination with NAC, could provide a new therapeutic strategy to combat AILI, especially in treating patients
admitted after NAC treatment is no longer effective. Based on these preliminary data, we propose that Sdc1 is
a critical endogenous factor that halts the perpetuation of liver injury and facilitates liver repair in AILI. This
hypothesis will be tested in 3 specific aims. Aim 1 will define how Sdc1 is released from hepatocytes during
AILI and establish that discrete structural motifs in Sdc1 HS provide protection against AILI. Aim 2 will
elucidate the biological mechanisms of how Sdc1 halts the progression of AILI. Aim 3 will determine how Sdc1
enhances hepatocyte proliferation and facilitates liver repair in AILI. These studies are expected to establish a
new integrated pathway in liver injury and repair.

## Key facts

- **NIH application ID:** 10810655
- **Project number:** 5R01DK128455-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Pyong Woo Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,035
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810655

## Citation

> US National Institutes of Health, RePORTER application 10810655, HSPG Interactions in Liver Disease (5R01DK128455-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10810655. Licensed CC0.

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