# Lipid metabolites can both potentiate and treat alcoholic hepatitis

> **NIH NIH U01** · UNIVERSITY OF LOUISVILLE · 2020 · $241,366

## Abstract

Alcoholic Hepatitis (AH) is an important cause of morbidity, mortality, and health care costs. Only a limited
number (<25% of those who drink heavily) develop this more advanced liver disease. Thus, there must be
modifying factors that either prevent or facilitate disease activity/progression. Dietary fat represents a critical
macronutrient disease modifier for AH. The American diet has increased dramatically in omega 6-
polyunsaturated fat (PUFA) content and has a very imbalanced omega-6:omega-3 ratio. In pre-clinical rodent
models, dietary PUFA enriched in linoleic acid (LA), promotes alcohol-induced liver damage. Mice fed an
alcohol + high PUFA (LA) diet generate toxic oxidized products of linoleic acid metabolism (OXLAMs) as well
as a highly reactive and toxic aldehyde lipid peroxidation product, (i.e., acrolein), which causes ER stress and
liver injury. This high PUFA diet plus alcohol in rodents also causes gut dysbiosis and decreases levels of the
critical short chain fatty acid, butyrate. We postulate that human subjects with AH will have (i) increased
levels of the lipid peroxidation product, acrolein (toxic aldehyde), (ii) increased levels of OXLAMs, and
(iii) altered gut flora with decreased fecal levels of butyrate and butyrate producing bacteria, all of
which correlate with severity of liver injury. We also postulate that certain lipid products (resolvins,
butyrate) will be therapeutic in AH. We address this hypothesis with three specific aims using unique human
samples generated through the NIAAA-funded U01-consortium in AH.
Specific Aim #1: Determine whether levels of acrolein metabolites and adducts in serum/urine/tissue are
elevated in AH, and correlate these levels with biomarkers of gut permeability, hepatic cell death/injury and
disease severity.
Specific Aim #2: Determine whether serum levels of OXLAMS are elevated in human AH, and correlate
those levels with biomarkers of severity of AH, hepatocyte death, and gut permeability. Determine whether
serum levels of resolvins are decreased in AH and whether resolvin administration to AH blood ex vivo
decreases proinflammatory cytokines.
Specific Aim #3: Determine fecal levels of short-chain fatty acids (focusing on butyrate) in patients with AH,
and determine abundance of butyrate-producing bacteria in patients with acute AH and after recovery with
abstinence. We will also determine the effects of different doses of butyrate on ex-vivo cytokine production in
AH patients.
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## Key facts

- **NIH application ID:** 9983526
- **Project number:** 5U01AA026936-03
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Swati Joshi-Barve
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,366
- **Award type:** 5
- **Project period:** 2018-09-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983526

## Citation

> US National Institutes of Health, RePORTER application 9983526, Lipid metabolites can both potentiate and treat alcoholic hepatitis (5U01AA026936-03). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9983526. Licensed CC0.

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