# Elucidating the Role of Very-long-chain Polyunsaturated Fatty Acids in Retinal Health and Disease

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $30,000

## Abstract

Abstract: The effect of a novel fish oil supplement enriched in very-long-chain (C≥24)
polyunsaturated fatty acids (VLCPUFAs) on cardiometabolic risk factors and visual function will
be assessed in this bench-to-bedside proposal. VLCPUFAs play important tissue specific roles
that cannot be fulfilled by more abundant shorter-chain FAs. The ELOVL2 enzyme in the liver is
responsible for converting docosapentaenoic acid (DPA: 22:5 n-3) to tetracosapentaenoic acid
(TPA: 24:5 n-3), which is further extended in 2-carbon steps to chain lengths greater than 36
carbons by the ELOVL4 enzyme in the retina, brain and testis. Heterozygous ELOVL4 mutations
lead to Stargardt-like macular dystrophy, a progressive form of macular degeneration that causes
blindness in young adults. Some ELOVL4 mutations lead to spinocerebellar ataxia. VLCPUFAs
are also important in spermatogenesis and have been proposed to be involved in male infertility.
 Fish oil-derived PUFAs (EPA: 20:5 n-3, DHA: 22:6 n-3) exert potent anti-inflammatory and
cardiometabolic benefits, but in clinical trials like AREDS2 they have not consistently slowed the
progression of age-related macular degeneration (AMD). Standard fish oils, however, contain less
than 1% (w:w) VLCPUFAs. Retinal levels of VLCPUFAs decrease with age and are especially low
in AMD patients. Because ELOVL2 expression markedly decreases with aging due to promoter
methylation, we hypothesized that the age-related declined in VLCPUFAs could be ameliorated
with a dietary supplement containing TPA. We recently showed in aged mice that dietary
supplementation with a novel fish oil enriched in VLCPUFAs (C24-C28) not only improved retinal
function, but also had beneficial effects on cardiometabolic risk factors (decreased plasma lipids
and improved insulin-sensitivity). Some of these beneficial effects are possibly due to the ability
of VLCPUFAs to act as PPAR-agonists. We found that TPA was a more potent PPAR (α and γ)
agonist than EPA and DHA. Our results, therefore, suggest that VLCPUFA-rich fish oil could be
more effective than EPA, a currently approved treatment for cardiovascular disease prevention
and could also be a new nutritional therapy for AMD.
 For our basic science aims, we plan to examine in more detail the mechanism of action
of VLCPUFAs. EPA/DHA are known to exert their anti-inflammatory and insulin-sensitizing effects
by G-protein-coupled receptors (GPRs). Drs. Danner and Wang, NHLBI and CC associate
investigators, will identify possible GPR targets for chemically synthesized VLCPUFA and
elucidate their signaling pathways, using specific GPR knockdown and knockout cells expressing
reporter genes. Dr. Bernstein, an extramural co-investigator, will compare chemically synthesized
VLCPUFA versus EPA/DHA, as well as VLCPUFA-rich fish oil versus regular EPA/DHA-rich fish
oil, for their ability to slow retinal degeneration in Elovl4 conditional knockout mice. Dr. Remaley’s
lab at NHLBI will perform a similar study in ApoE-KO mi...

## Key facts

- **NIH application ID:** 11043157
- **Project number:** 3R01EY034497-02S1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** PAUL STEVEN BERNSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $30,000
- **Award type:** 3
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11043157

## Citation

> US National Institutes of Health, RePORTER application 11043157, Elucidating the Role of Very-long-chain Polyunsaturated Fatty Acids in Retinal Health and Disease (3R01EY034497-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11043157. Licensed CC0.

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