Deletion of membrane-type frizzled-related protein (MFRP) or adiponectin receptor 1 (AdipoR1) results in selective fatty acid synthesis impairments and photoreceptor cell degeneration in mice

Abstract

Purpose : Membrane-type frizzled-related protein (MFRP) and adiponectin receptor 1 (AdipoR1) are vital to the maintenance of a healthy retinal lipidome. Using Mfrp^rd6 and Adipor1^-/- mice, we found that both retinal degeneration models result in a reduction of phospholipids containing docosahexaenoic acid (DHA; 22:6) and very long-chain polyunsaturated fatty acids (VLC-PUFAs). Given that these lipids are essential for proper vision, we aimed to determine the relative amounts of ω-3 and ω-6 fatty acid intermediates in Mfrp^rd6 and Adipor1^-/-.

Methods : The retina and RPE-eyecups of 6-week-old Mfrp^rd6, Adipor1^-/-, and wild-type (C57BL6/J) mice were harvested and incubated for 7 days in a control medium or medium containing DHA-d5, EPA-d5, AA-d8, or 38:6n3-d6. Lipid extraction was performed on day 7 followed by alkaline hydrolysis. The relative lipid abundance of ω-3 and ω-6 fatty acid intermediates were analyzed via LC-MS/MS.

Results : Fatty acid analysis showed a decrease in fatty acids 24:6n3 to 36:6n3 in Mfrp^rd6 and Adipor1^-/- retina. In RPE, 32:6n3 and 34:6n3 were specifically decreased. Interestingly, Mfrp^rd6 had elevated levels of 22:5n3 and 24:5n3 in the retina. In contrast, Adipor1^-/- retina had decreased levels of 22:5n3 and 24:5n3. Additionally, 20:4n6, 22:4n6, and 24:4n6 were increased in Mfrp^rd6 retina.

Conclusions : Our study demonstrates that both Mfrp^rd6 and Adipor1^-/- have depleted levels of VLC-PUFAs from 24:6n3 onwards, suggesting a decreased ability to synthesize ELVs, which require precursors 32:6n3 and 34:6n3. Given the buildup of 24:5n3 in Mfrp^rd retina, the conversion of 24:5n3 to 24:6n3 seems to be impaired in Mfrp^rd6 mice, contrasting from Adipor1^-/- with PUFAs low from 20:5n3 to 36:6n3. In Mfrp^rd, there were increased levels of arachidonic acid and its downstream products. Retinal degeneration involves differences in ω-3 and ω-6 biosynthesis with a prevalence of the former.

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