# 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 · $390,875

## Abstract

Very long-chain polyunsaturated fatty acids (VLC-PUFAs) are non-dietary lipids that are uniquely found
in the retina and just a few other tissues in the human body. These unusual C26-C38 n-3 and n-6 lipids are
synthesized from long-chain polyunsaturated fatty acid (LC-PUFA) dietary precursors through the action of the
ELOVL4 fatty acid elongase. Enhanced membrane fluidity contributed by LC-PUFAs and VLC-PUFAs is thought
to be essential for the maintenance of the highly curved membrane disks of the photoreceptor outer segments
and to facilitate photoreceptor synaptic transmission. Autosomal dominant mutations in ELOVL4 lead to a form
of Stargardt macular dystrophy (STGD3) that shares many features with dry age-related macular degeneration
(AMD), and we and others have shown that conditional knockouts of rod and cone Elovl4 lead to depletion of
retinal VLC-PUFAs and eventual retinal functional and structural abnormalities in mouse models.
 Although ELOVL4 variants have not been associated with AMD risk, the protective effects of diets high
in lipid precursors of n-3 VLC-PUFAs against STGD3 and AMD led to us to examine the influence of diet on
retinal VLC-PUFA levels and n-3/n-6 ratios in health and disease. We have reported that dietary consumption
of VLC-PUFA precursors strongly influences n-3/n-6 ratios and VLC-PUFA content in normal human retinas and
that VLC-PUFA profiles are distinctly abnormal in AMD donors even outside of the macula. These findings
suggest that abnormalities of VLC-PUFA metabolism are intimately associated with macular degeneration and
that strategies to increase VLC-PUFA levels by supplementation could help slow the degeneration process.
 Surprisingly, the obvious therapeutic intervention of bypassing local retinal synthesis of VLC-PUFAs by
administering preformed VLC-PUFAs exogenously had never been tried in living organisms because, until
recently, there have never been adequate supplies of these lipids to perform these experiments, even in mice.
Although synthesis of VLC-PUFAs has been reputed to be very difficult, we initiated a collaboration with lipid
chemistry specialists at the University of Utah who developed improved schemes that allow for straightforward
scale-up to produce sufficient quantities of pure n-3 and n-6 VLC-PUFAs (unlabeled, fluorinated, or deuterated)
for animal studies and even eventual human trials. We have generated exciting initial data that show that an
orally administered synthetic VLC-PUFA (32:6 n-3) is selectively targeted to the retina and the RPE after acute
and chronic gavage feeding in mice and that wild-type mice and a mouse model of VLC-PUFA dysfunction show
functional improvements in their ERGs and visual performance. With our unique access to sufficient quantities
of an array of n-3 and n-6 VLC-PUFAs, we are eager to continue to test our fundamental hypothesis that VLC-
PUFAs are key compounds for the maintenance of photoreceptor function in the retina in both health and disease
state...

## Key facts

- **NIH application ID:** 10862795
- **Project number:** 5R01EY034497-02
- **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:** $390,875
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862795

## Citation

> US National Institutes of Health, RePORTER application 10862795, Elucidating the Role of Very-long-chain Polyunsaturated Fatty Acids in Retinal Health and Disease (5R01EY034497-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862795. Licensed CC0.

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