# Pathogenic role of hepatocyte-derived high-mobility group box-1 isoforms as potential therapeutic targets to prevent and/or resolve liver fibrosis

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $476,043

## Abstract

ABSTRACT
Identifying and understanding the mechanisms whereby key hepatocyte-derived danger signals drive the
fibrogenic response to liver injury remains a current challenge to make progress in this field of research. Our
recent studies revealed that high-mobility group box-1 (HMGB1) is up-regulated, oxidized and secreted largely
by damaged hepatocytes. Therefore, since hepatocyte-derived HMGB1 can communicate injury to neighboring
cells, specific isoforms could target hepatic stellate cells, the key pro-fibrogenic cell type in the liver, to elicit
scarring.PreliminaryresultssupportingthisapplicationshowthatinductionofHMGB1expressioncorrelates
with fibrosis stage in patients and mice. Importantly, hepatocyte-derived HMGB1 undergoes unique post-
translational modifications in response to oxidant stress. While fully reduced followed by oxidized or disulfide
HMGB1 significantly rise at peak fibrosis; yet, sulfonate HMGB1 appears mostly during fibrosis resolution
whereas the other isoforms decline. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protects from fibrosis
progression. Administration of oxidized HMGB1 enhances liver fibrosis more than reduced HMGB1. In contrast,
injection of sulfonate HMGB1 lowers collagen-I and induces stellate cell apoptosis, critical for fibrosis resolution.
Moreover, ablation of the HMGB1 receptor for advanced glycation end-products (Rage) in stellate cells blocks
the HMGB1-mediated collagen-I increase in vitro and RAGE neutralization or ablation in stellate cells
(RageΔHSC) prevents scarring in vivo. While we demonstrate that the oxidized HMGB1 isoforms are mostly
produced by damaged hepatocytes, their specific contribution to fibrosis progression and/or resolution is still
undefined. Our central hypothesis is that the redox-sensitive dynamic changes in hepatocyte-derived HMGB1
isoforms signal via RAGE-dependent mechanisms to drive the stellate cell pro-fibrogenic phenotype and fate,
therefore contributing to the progression and/or resolution of liver fibrosis. In Aim 1, to determine the HMGB1
isoforms’ affinity and potential competition among them for RAGE, we will: 1) study the binding ability and
kinetics of each HMGB1 isoform to RAGE with surface plasmon resonance; 2) identify the precise amino acid
residues from each HMGB1 isoform that interact with RAGE by nuclear magnetic resonance spectroscopy; and
3) prove the ligand-receptor interaction using in vitro and in vivo approaches. In Aim 2, to identify how the
HMGB1 isoforms signal via RAGE-dependent mechanisms to drive the stellate cell pro-fibrogenic phenotype
and fate, we will use complementary in vitro systems and in vivo approaches. Fibrosis progression and
resolutionwillbemonitoredbymagneticresonanceelastographyandconventionalparametersofliverinjury.
Next, the signals transduced by each isoform in stellate cells via RAGE to up-regulate collagen-I and drive the
cell fate will be identified with a proteomics approach followed by in vitro validation; then, the key s...

## Key facts

- **NIH application ID:** 9966974
- **Project number:** 5R01DK111677-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Natalia Nieto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $476,043
- **Award type:** 5
- **Project period:** 2017-07-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966974

## Citation

> US National Institutes of Health, RePORTER application 9966974, Pathogenic role of hepatocyte-derived high-mobility group box-1 isoforms as potential therapeutic targets to prevent and/or resolve liver fibrosis (5R01DK111677-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9966974. Licensed CC0.

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