Grant Abstract: B-to-B: Elucidating the Role of Very-long-chain Polyunsaturated Fatty Acids in Retinal Health and Disease

Grant Number: 1R01EY034497-03
PI Name: Bernstein
Project Title: B-to-B: Elucidating the Role of Very-long-chain Polyunsaturated Fatty Acids in Retinal Health and Disease

Abstract: Very long-chain polyunsaturated fatty acids (VLC-PUFAs) are non-dietary lipids that are uniquely found in the retina and just a few other tissues in the human body. These unusual C26-C38 n-3 and n-6 lipids are synthesized from long-chain polyunsaturated fatty acid (LC-PUFA) dietary precursors through the action of the ELOVL4 fatty acid elongase. Enhanced membrane fluidity contributed by LC-PUFAs and VLC-PUFAs is thought to be essential for the maintenance of the highly curved membrane disks of the photoreceptor outer segments and to facilitate photoreceptor synaptic transmission. Autosomal dominant mutations in ELOVL4 lead to a form of Stargardt macular dystrophy (STGD3) that shares many features with dry age-related macular degeneration (AMD), and we and others have shown that conditional knockouts of rod and cone Elovl4 lead to depletion of retinal VLC-PUFAs and eventual retinal functional and structural abnormalities in mouse models. Although ELOVL4 variants have not been associated with AMD risk, the protective effects of diets high in lipid precursors of n-3 VLC-PUFAs against STGD3 and AMD led to us to examine the influence of diet on retinal VLC-PUFA levels and n-3/n-6 ratios in health and disease. We have reported that dietary consumption of VLC-PUFA precursors strongly influences n-3/n-6 ratios and VLC-PUFA content in normal human retinas and that VLC-PUFA profiles are distinctly abnormal in AMD donors even outside of the macula. These findings suggest that abnormalities of VLC-PUFA metabolism are intimately associated with macular degeneration and that strategies to increase VLC-PUFA levels by supplementation could help slow the degeneration process. Surprisingly, the obvious therapeutic intervention of bypassing local retinal synthesis of VLC-PUFAs by administering preformed VLC-PUFAs exogenously had never been tried in living organisms because, until recently, there have never been adequate supplies of these lipids to perform these experiments, even in mice. Although synthesis of VLC-PUFAs has been reputed to be very difficult, we initiated a collaboration with lipid chemistry specialists at the University of Utah who developed improved schemes that allow for straightforward scale-up to produce sufficient quantities of pure n-3 and n-6 VLC-PUFAs (unlabeled, fluorinated, or deuterated) for animal studies and even eventual human trials. We have generated exciting initial data that show that an orally administered synthetic VLC-PUFA (32:6 n-3) is selectively targeted to the retina and the RPE after acute and chronic gavage feeding in mice and that wild-type mice and a mouse model of VLC-PUFA dysfunction show functional improvements in their ERGs and visual performance. With our unique access to sufficient quantities of an array of n-3 and n-6 VLC-PUFAs, we are eager to continue to test our fundamental hypothesis that VLC- PUFAs are key compounds for the maintenance of photoreceptor function in the retina in both health and disease states. We will do this by more fully exploring the mechanisms underlying the protective effects of exogenous VLC-PUFAs in the retina and RPE in novel animal models, in cell culture, and in model membranes.


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