# Essential Role of Very Long Chain Fatty Acids in Retinal Function

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $351,625

## Abstract

Abstract
Very long chain fatty acids (VLC-FA, ≥ C28) are synthesized by the Elongation of Very Long Chain Fatty
Acids-4 (ELOVL4) enzyme and are essential for life such that depletion of tissue VLC-FA (due to knockout of
ELOVL4) causes neonatal lethality. The ELOVL4 protein is expressed in the retina, Meibomian glands, brain,
skin, and testes. In each of these tissues, the enzyme makes two different classes of VLC-FA. One class is
VLC-saturated fatty acids (VLC-SFA) that are found mainly in the skin, brain, Meibomian glands and tear film.
The other is VLC-polyunsaturated fatty acids (VLC-PUFA) that are found in the retina, testes and sperm. Since
VLC-FA are essential for the normal function of these tissues, mutations in ELOVL4 cause distinct tissue-
specific disorders like Stargardt-like macular dystrophy (STGD3), spinocerebellar ataxia-34 (SCA34), skin
pathologies, seizures and death. However, the mechanisms by which one tissue makes mainly VLC-SFA and
the other VLC-PUFA, and how the VLC-FA exert their importance in each tissue remain unknown. We seek to
understand the molecular basis of this phenomenon with the goal of developing therapeutic targets for
attenuating disease progression. Our lab and others have shown that conditional deletion of retinal Elovl4 or
expression of the mutant Elovl4 leads to depletion of VLC-SFA and VLC-PUFA, which affect retinal structure
and function. We also showed that the STGD3 mutant ELOVL4 lacks VLC-PUFA biosynthesis and exerts a
dominant negative effect on wild type ELOVL4 (WT ELOVL4) in vitro and in vivo causing decreased VLC-FA
biosynthesis. These suggest that VLC-FA are necessary for maintenance of photoreceptor health and function.
To understand how one set of mutations causes vision loss and another causes ataxia, we successfully
generated a Long Evans (LE) rat knock-in model of the SCA34 ELOVL4 mutation (c.736T>G) that
recapitulates the human disorder. Consequently, we now have animal models of STGD3 and SCA34. We
hypothesize that tissue-specific factors determine which type of fatty acid is made in specific tissues and that
the pathological differences found in patients with STGD3 and SCA34 result from differences in the types of
VLC-FAs produced directly by the mutant enzymes or from effects of the mutant enzymes on VLC-FA
produced by the wild type ELOVL4 enzyme. We propose two specific aims: 1) To determine how different
ELOVL4-expressing tissues control the VLC-SFA and VLC-PUFA biosynthetic activity of ELOVL4. 2) To
determine how the different ELOVL4 mutations affect the quality and quantity of the VLC-FA that they
synthesize. The results would provide better mechanistic insight into the relative contributions of the depletion
of VLC-FA and the mutant ELOVL4 in the progression of the mutant ELOVL4 disorders. This could potentially
provide an immediate positive impact by paving the way for development of potential therapeutic approaches
to rescue these disorders.

## Key facts

- **NIH application ID:** 10186758
- **Project number:** 5R01EY030513-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Martin-Paul Agbaga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,625
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186758

## Citation

> US National Institutes of Health, RePORTER application 10186758, Essential Role of Very Long Chain Fatty Acids in Retinal Function (5R01EY030513-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10186758. Licensed CC0.

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