# Identifying an immunoregulatory axis for FGF21 in alcohol consumption

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $537,587

## Abstract

PROJECT SUMMARY/ABSTRACT
 Alcohol abuse is a major health concern with a recently alarming increase in prevalence. Among the various
complications associated with alcohol use disorder (AUD), alcohol-associated liver disease (ALD) is the most
common and devastating. Mounting evidence supports a central role for inflammation and metabolic dysfunction
in ALD. The long-term goal of this work is to understand the metabolic consequences of liver inflammation on
alcohol consumption and ALD progression, and leverage this insight to develop novel treatment strategies. We
have identified and characterized multiple points of crosstalk between interferon regulatory factor 3 (IRF3), a
master regulator of innate immunity, and hepatic metabolism. Our preliminary data show that alcohol-induced
IRF3 suppresses maximal fibroblast growth factor 21 (FGF21) expression and secretion by the liver. Using a
novel phospho-mimetic mutant of IRF3, we found that transcriptionally active IRF3 abolishes alcohol-induced
FGF21 secretion, while IRF3 deficiency enhances endogenous FGF21 secretion. Although IRF3 itself does not
act as a transcriptional repressor of Fgf21, its metabolic effects are mediated through its transcriptional target,
PLAGL1. The overall goal of this proposal is to identify the mechanisms responsible for IRF3-mediated FGF21
suppression and its impact on alcohol consumption and ALD. Our central hypothesis is that alcohol-induced
IRF3 triggers transcription of PLAGL1, which functions as a novel repressor of Fgf21 expression, ultimately
limiting its secretion. By targeting the IRF3-PLAGL1 inhibitory axis, we can release the brakes on Fgf21
transcription, increase endogenous FGF21 secretion, and enhance its beneficial effects on alcohol consumption
and liver metabolism. In this proposal we will define the impact of IRF3-mediated FGF21 suppression on alcohol
preference, motor impairment and sedation, as well as alcohol-induced steatosis and insulin resistance. Lastly,
we will determine the mechanism by which the IRF3-PLAGL1 inhibitory axis regulates FGF21 levels, and
subsequently alcohol consumption and ALD. Collectively, these studies will greatly advance our understanding
of the metabolic consequences of inflammation on ALD progression. FGF21 is currently in clinical trials for
obesity-induced metabolic dysfunction, and its beneficial role in AUD and ALD is undeniable. This work presents
a critical opportunity to enhance the secretion of endogenous FGF21 in response to metabolic stressors such
as obesity-inducing carbohydrate-rich diets and alcohol consumption.

## Key facts

- **NIH application ID:** 11048195
- **Project number:** 1R01AA031460-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Suraj J Patel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $537,587
- **Award type:** 1
- **Project period:** 2024-09-20 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11048195

## Citation

> US National Institutes of Health, RePORTER application 11048195, Identifying an immunoregulatory axis for FGF21 in alcohol consumption (1R01AA031460-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11048195. Licensed CC0.

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