# Studies of retinyl ester hydrolase in the visual cycle

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $316,619

## Abstract

PROJECT SUMMARY/ABSTRACT
 Light-induced isomerization of 11-cis retinal, the chromophore of visual pigments, to all-trans retinal
initiates vision. Efficient recycling of 11-cis retinal through the visual cycle is essential for the formation of visual
pigments and maintaining normal vision. A key step in the visual cycle is the conversion of all-trans retinyl ester
to 11-cis retinol, catalyzed by RPE65, the retinol isomerase. Documented studies have shown that retinoids are
largely stored as all-trans retinyl ester, the substrate of the isomerase RPE65, in lipid droplets (retinosomes) in
the RPE. However, RPE65 is located in the ER and not near the lipid droplets. It is unknown how hydrophobic
all-trans retinyl ester, the substrate of RPE65, is transported from lipid droplets to the ER. This represents an
important knowledge gap in the visual cycle. A retinyl ester hydrolase (REH) may be present in lipid droplets to
mobilize all-trans retinyl ester to provide the substrate for the RPE65 isomerase in the ER. Patatine-like
phospholipase domain containing protein 2 (PNPLA2) is known as an adipose triglyceride lipase with an REH
activity in the liver. Its function in the RPE and its association with the visual cycle have not been investigated.
Our preliminary studies identified PNPLA2 in the RPE and in lipid droplets. Importantly, PNPLA2-/- mice showed
declined ERG responses and delayed regeneration of visual pigments. PNPLA2 KO also resulted in reduced
11-cis retinal generation and increased levels of all-trans retinyl ester in the RPE, suggesting a decreased
isomerase activity. These findings suggest a potential role of PNPLA2 in the visual cycle. We hypothesize that
PNPLA2 functions as an REH in the RPE and mobilizes all-trans retinyl ester from lipid droplets to provide
sufficient substrate for the RPE65 isomerase in the ER to generate 11-cis retinol. In this project, we will define
the role of PNPLA2 in maintaining the visual cycle and normal vision. We will use RPE-specific PNPLA2
conditional KO mice to study the impacts of PNPLA2 KO on retinal function, retinal degeneration, visual pigment
formation and regeneration of 11-cis retinal. We also plan to determine if co-expression of PNPLA2 together with
RPE65 in the RPE of RPE65-/- mice by gene delivery will enhance the effect of RPE65 on restoring visual
function, visual pigment formation and 11-cis retinal regeneration, compared to RPE65 gene delivery alone. We
will also elucidate the mechanism by which PNPLA2 promotes the RPE65 isomerase activity and accelerates
11-cis retinal regeneration in the visual cycle. We will investigate if knockout of PNPLA2 in RPE cells will
decrease, while overexpression of PNPLA2 will promote, isomerase activity of RPE65 and reduce lipid droplets
in RPE cells. We will also determine if a PNPLA2 activator will promote, while a PNPLA2 inhibitor will inhibit the
isomerase activity in RPE cells. These studies have potential to identify a missing component in the visua...

## Key facts

- **NIH application ID:** 10547900
- **Project number:** 7R01EY032930-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jian-Xing Jay Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $316,619
- **Award type:** 7
- **Project period:** 2021-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547900

## Citation

> US National Institutes of Health, RePORTER application 10547900, Studies of retinyl ester hydrolase in the visual cycle (7R01EY032930-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10547900. Licensed CC0.

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