Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver.

Matthew L Batten,Russell N Van Gelder,Daniel Possin,Tadao Maeda,Yoshikazu Imanishi,Krzysztof Palczewski,Alexander R Moise,Wolfgang Baehr,Daniel C Tu,Darin Bronson

doi:10.1074/jbc.m312410200

Matthew L Batten, Russell N Van Gelder + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m312410200

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Abstract

Lecithin-retinol acyltransferase (LRAT), an enzyme present mainly in the retinal pigmented epithelial cells and liver, converts all-trans-retinol into all-trans-retinyl esters. In the retinal pigmented epithelium, LRAT plays a key role in the retinoid cycle, a two-cell recycling system that replenishes the 11-cis-retinal chromophore of rhodopsin and cone pigments. We disrupted mouse Lrat gene expression by targeted recombination and generated a homozygous Lrat knock-out (Lrat-/-) mouse. Despite the expression of LRAT in multiple tissues, the Lrat-/- mouse develops normally. The histological analysis and electron microscopy of the retina for 6-8-week-old Lrat-/- mice revealed that the rod outer segments are approximately 35% shorter than those of Lrat+/+ mice, whereas other neuronal layers appear normal. Lrat-/- mice have trace levels of all-trans-retinyl esters in the liver, lung, eye, and blood, whereas the circulating all-trans-retinol is reduced only slightly. Scotopic and photopic electroretinograms as well as pupillary constriction analyses revealed that rod and cone visual functions are severely attenuated at an early age. We conclude that Lrat-/- mice may serve as an animal model with early onset severe retinal dystrophy and severe retinyl ester deprivation.

Highlights

B These authors contributed to this work. e Recipient of Research to Prevent Blindness Career Development Award. h Research to Prevent Blindness Senior Investigator. k To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Box 356485, Seattle, WA 981956485
In the retinal pigmented epithelium, Lecithin-retinol acyltransferase (LRAT) plays a key role in the retinoid cycle, a two-cell recycling system that replenishes the 11-cis-retinal chromophore of rhodopsin and cone pigments
We conclude that Lrat؊/؊ mice may serve as an animal model with early onset severe retinal dystrophy and severe retinyl ester deprivation

Summary

Introduction

B These authors contributed to this work. e Recipient of Research to Prevent Blindness Career Development Award. h Research to Prevent Blindness Senior Investigator. k To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Box 356485, Seattle, WA 981956485. In the rod and cone photoreceptor outer segments, 11-cis-retinal recombines with opsins to form rhodopsin and cone pigments (for review, see Ref. 8). Patients carrying the S175R LRAT null gene developed normally, suggesting that the lack of LRAT in the liver and other tissues had no deleterious effects. Their visual functions are severely attenuated, causing early onset severe retinal dystrophy. The RPE of LratϪ/Ϫ mice is devoid of all-trans-retinol or all-trans-retinyl esters, photoreceptors have no functional rhodopsin, and electroretinogram (ERG) responses are highly attenuated. LratϪ/Ϫ mice are an important experimental model for human retinal dystrophies and for vitamin A deprivation

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