# Neuregulin-4 Signaling in Hepatocytes Defines an Endocrine Checkpoint for NASH and HCC Progression

> **NIH NIH F30** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $41,071

## Abstract

PROJECT SUMMARY (ABSTRACT)
The obesity epidemic has greatly increased the incidence of non-alcoholic fatty liver disease (NAFLD), the
condition now identified as the leading cause of chronic liver injury in the United States. NAFLD is defined by
excess accumulation of lipids in the liver, also referred to as steatosis. Prolonged fatty liver is highly associated
with increased cell injury, inflammation, regrowth, and fibrosis, a stage referred to as non-alcoholic
steatohepatitis (NASH). Advanced NASH often leads to cirrhosis, an end-stage liver condition which
necessitates liver transplant in patients. Furthermore, repeated insults to liver tissue results in accelerated cell
turnover, raising the risk of mutations and progression to hepatocellular carcinoma (HCC), the third leading
cause of cancer-related death worldwide. Despite a clear association between NAFLD and progression to
these deadly sequelae, the pathogenesis of these conditions remains poorly understood. The impending
contributions that rising obesity rates will make to NAFLD prevalence makes elucidating its pathogenesis
urgent.
Our group previously characterized a novel adipose-secreted protein Neuregulin-4 (Nrg4) which targets liver to
improve steatosis. Interestingly, Nrg4 expression is downregulated in NASH, implying a possible role of Nrg4 in
regulating NASH pathogenesis. Our preliminary studies showed that Nrg4 deficiency renders mice susceptible
to NASH. These mice exhibited increased apoptosis and necroptosis in liver, which are central pathways in the
pathogenesis of NASH. Interestingly, these mice displayed lowered levels of c-FLIPL, a key regulator of these
pathways. Our findings indicate Nrg4 may prevent NASH through attenuation of cell death pathways. Despite
these provocative findings, the potential for Nrg4 signaling to block the progression of NAFLD to NASH and
HCC remains unexplored. The goal of this study is to unravel the role of Nrg4 signaling in protecting from
NASH and HCC pathogenesis. Here, we propose to elucidate the effect of Nrg4 on NAFLD progression with
the following aims: Aim 1 will evaluate the effect of excess Nrg4, in a transgenic context, and also exogenously
administered, in alleviating NASH in mice. Aim 2 will utilize recombinant Nrg4 treatment of primary
hepatocytes to dissect the signaling pathways regulating Nrg4 attenuation of cell death, and harness viral
expression to test if modulating these pathways could rescue Nrg4 deficient mice from NASH. Aim 3 will
evaluate the potential for Nrg4 to prevent NASH-associated HCC using both Nrg4 transgenic and knockout
models.
In summary, we anticipate these aims will potentially uncover a novel endocrine pathway which protects from
NASH and HCC, and may provide a therapy for these conditions.

## Key facts

- **NIH application ID:** 9846214
- **Project number:** 5F30DK117615-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Henry Kuang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,071
- **Award type:** 5
- **Project period:** 2018-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846214

## Citation

> US National Institutes of Health, RePORTER application 9846214, Neuregulin-4 Signaling in Hepatocytes Defines an Endocrine Checkpoint for NASH and HCC Progression (5F30DK117615-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9846214. Licensed CC0.

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