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Danielle Swinkels, Yannick Das, Sai Kocherlakota, Bok Kyoo jun, Frédéric Vaz, Paul van Veldhoven, Nicolas G Bazan, Myriam Baes; Systemic supply of DHA is essential for retinal DHA levels and retinal integrity in mice. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4114 – F0351.
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Patients deficient in peroxisomal β-oxidation, which is essential for the synthesis of DHA (C22:6n-3) and the breakdown of VLC-PUFAs, present with retinopathy and reduced plasma DHA. A mouse model lacking peroxisomal multifunctional protein 2 (Mfp2-/- mice) also develops an early onset retinal decay, accompanied by reduced plasma and retinal DHA. We hypothesized that a reduced supply of DHA causes the Mfp2-/- retinal phenotype.
To define the contribution of local versus systemic supply of DHA for the neural retina, we investigated the retina of photoreceptor-specific Mfp2-/- (Crx-Mfp2-/-) and of liver specific Pex5-/- mice, which lack all peroxisomal functions in hepatocytes. Next, a 0.1% DHA or control diet was fed to Mfp2+/- pregnant female mice and their offspring until sacrifice at 4w, 8w or 16w. Mfp2-/- mice and controls were analyzed for retinal function via full-field ERG, for lipid composition of NR and plasma with LC-MS/MS and GC, and histologically using retinal sections and RPE flatmounts.
Alb-Pex5-/- mice displayed reduced plasma and retinal DHA levels, impaired ERG responses and shortened POS at 8w. In contrast, DHA levels and retinal morphology were normal in Crx-Mfp2-/- mice. DHA supplementation to Mfp2-/- mice increased plasma DHA even above levels in WT mice on control diet. Lipidome analysis showed normalization of DHA-containing phospholipids in the NR, such as LPC(22:6) and PC(44:12). Phospholipid species containing ultra-long-chain-PUFAs (>C36) still accumulated. Remarkably, until the age of 8w, the retinal morphology considerably improved with regard to: POS length, photoreceptor cell death and maintenance of the RPE honeycomb pattern, and inflammation was dampened. However, visual function improved only at the age of 4 weeks and deteriorated subsequently. Despite the initial rescue of retinal integrity, DHA supplementation could not prevent a complete retinal degeneration at 16w.
Our data prove that systemic supply of DHA is essential for the DHA pool in the NR. DHA supplementation rescues the retinal morphology of Mfp2-/- mice at an early age, but cannot prevent the retinal demise at later age. We hypothesize that the supplied DHA is converted into the protective lipid mediator Neuroprotectin D1 but that accumulating ultra-long-chain-PUFAs are toxic.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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