# Role of n3 PUFAs and inflammation-resolving lipid mediator, RvD1, in alcoholic liver disease

> **NIH NIH P50** · UNIVERSITY OF LOUISVILLE · 2022 · $264,780

## Abstract

Alcoholic liver disease (ALD) is a major and increasing health problem in the US (especially in Kentucky) and
worldwide. In spite of the magnitude of this problem, there is no FDA-approved therapy for any stage of ALD. In
addition, the mechanisms and regulators of the disease progression and severity are not well understood. Dietary
fats play an important interactive role with alcohol consumption in ALD pathogenesis, however, the role of n3
PUFAs in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial in ALD, in part, via
n3-PUFA-derived pro-resolving mediators which facilitate inflammation resolution, improvement in the gut-liver
axis, and subsequent attenuation of liver injury. We propose that resolvin D1 (RvD1) is a potent therapeutic
agent in severe ALD acting via RvD1-FPR2-NEAT1 signaling to suppress pro-inflammatory cytokines and to
promote repair of hepatocellular damage, in part, via enhancement of pro-restorative macrophages. We
postulate that compromised inflammation resolution due to impaired RvD1 production/signaling is one of the
critical nutritional contributing factors to the progressive ALD and severity of alcoholic hepatitis (AH) in humans.
The Specific Aims of the proposal are: Aim 1. To test whether n3 PUFAs exert beneficial effects on EtOH-
associated liver injury/inflammation by enhancing the effectiveness of inflammation resolution and by
repair of hepatocellular damage through increase in n3-PUFA-derived specialized pro-resolving mediators
promoting
(SPMs), and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling and
reprogramming pro-inflammatory macrophages into a pro-restorative phenotype. Wild Type (WT), Fpr2-/-,
Neat1-/-, and transgenic fat-1 mice (which are able to endogenously convert n6 to n3 PUFAs) will be used in this
Aim. We will also examine the therapeutic effectiveness of RvD1 utilizing a novel nanoparticle technology of
targeted RvD1 delivery examine the role n3-PUFAs
to the liver with plant-derived edible exosomes. Aim 2. To
and RvD1 in maintaining gut barrier integrity, and in the resolution of intestinal inflammation in experimental ALD.
We will: i) test in vivo, in animal models, and in vitro, in intestinal organoid culture, whether n3 PUFA or RvD1
improve intestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whether
disruption of the RvD1-FPR2 axis exacerbates, while blocking Neat1 signaling attenuates intestinal inflammation
and alterations in the gut barrier integrity; iii) test a novel therapeutic strategy of administering an engineered
bacteria strain to convert n6 to n3 PUFAs in the intestine and thus to attenuate gut barrier dysfunction in mice.
In Aim 3, we seek to translate and extend our findings in animal models to human ALD. Utilizing de-identified
human samples we will: i) determine effects of n3-PUFA dietary supplementation on plasma SPM levels, markers
of liver injury, systemic inflammation, and inte...

## Key facts

- **NIH application ID:** 10424375
- **Project number:** 5P50AA024337-07
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Irina A. Kirpich
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $264,780
- **Award type:** 5
- **Project period:** 2016-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424375

## Citation

> US National Institutes of Health, RePORTER application 10424375, Role of n3 PUFAs and inflammation-resolving lipid mediator, RvD1, in alcoholic liver disease (5P50AA024337-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10424375. Licensed CC0.

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