The importance of FADS2 in retinal function

Abstract

Purpose : Retinal lipid metabolism is essential for photoreceptor development, maintenance and function. DHA is the major polyunsaturated fatty acid (PUFA) that exerts antiangiogenic and neuroprotective functions in the retina. Depletion of retinal DHA affects retinal function and may contribute to aging eye diseases such as AMD. The retina avidly retains DHA, which makes it difficult to deplete through dietary intervention. Photoreceptors and glial cells express the Fatty Acid Desaturase 2 (FADS2) enzyme that mediates biosynthesis of DHA from dietary alpha-linolenic acid (ALA). Since FADS2 is the first and rate-limiting enzyme in the biosynthesis of essential PUFA, we tested the hypothesis that loss of FADS2 will cause loss of retinal DHA, affecting retina structure and function.

Methods : We generated Fads2 knockout mice (Fads2^-/-) by breeding heterozygous Fads2^+/- male and female C57BL6 mice on either an experimental (DHA-deficient) or regular (DHA-containing) diet. At weaning, the animals were maintained on their respective diets. At 4 months of age, we determined retinal function and structure by electroretinography (ERG) and fundoscopy. Whole eyes and retinas were harvested for immunohistochemistry and lipid analyses.

Results : Loss of FADS2 enzyme caused significant reduction in retinal scotopic a- and b-wave amplitudes in the Fads2^-/- compared to Fads2^+/+ mice raised on experimental diet. However, both Fads2^+/+ and Fads2^-/- mice raised on regular diet showed preservation of retinal function. The functional ERG changes correlate with retinal lesions in the Fads2^-/- compared to Fads2^+/+ mice raised on experimental diet, but not in mice raised on regular diet. Our lipid analyses confirmed decreased levels of retinal DHA in Fads2^-/- compared to Fads2^+/+ mice raised on experimental diet. However, animals raised on regular diet showed no differences in retinal DHA levels. Immunofluorescence analyses showed higher GFAP levels in Fads2^+/+ mice than Fads2^-/- that were fed the experimental diet, indicating reduced retinal glial cell activity in the absence of the FADS2 enzyme.

Conclusions : We developed an animal model that allowed us to manipulate retinal DHA levels in order to evaluate the effects of DHA loss on retina function. We showed that loss of FADS2, which mediates DHA biosynthesis from elongation and desaturation of dietary ALA, severely affects retinal lipid metabolism and DHA biosynthesis thereby causing functional retinal pathologies.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.