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Aurélie Cubizolle, laurent guillou, Claire Angebault, marie seveno, chantal cazevieille, Guy Lenaers, Philippe Brabet, Christian P Hamel; Human FATP1 overexpression in mouse retinal pigment epithelium.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5456.
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© ARVO (1962-2015); The Authors (2016-present)
In Retinal Pigment Epithelium (RPE), FATP1 co-localizes and may interact with RPE65 to slow the visual cycle by RPE65 inhibition. Our goal is to investigate the physiological role of FATP1 in the visual cycle and to understand how it can modify energy and lipid metabolism in the retina of a mouse model of FATP1 overexpression (FATP1Tg). Finally, we want to determine the therapeutic potential of FATP1 for Stargardt disease.
We worked on two mouse models: FATP1Tg overexpressing human FATP1 in RPE and wild type C57/Bl6J mice as control, both aged of 1, 3, 6, 9 and 12 months old. Our study was based on ex-vivo analysis using several technologies such as microscopy, SD-OCT, HPLC, enzymology and oxygraphy.
The kinetic of chromophore regeneration after photobleach showed a slow in the visual cycle and an increase of total retinoid in FATP1Tg compare to control, retinoid accumulated with aging from 20% to 40% more than in control. Also, the mRNA level of RPE65 decreased in FATP1Tg mice (roughly 50%).<br /> Histological analysis of FATP1Tg showed an increase in the thickness of the RPE (up to 15%) which presents large vacuoles. We first hypothesized retinyl ester accumulation in retinosomes (REST) in RPE. We observed a 2.5 fold increase of REST auto-fluorescence by two-photon microscopy. In close relation to lipid metabolism, mitochondrial respiration analysis in FATP1Tg retina showed a higher production of ATP by the β-oxidation. Mitochondrial respiration chain as well as enzyme activities involved in the TCA cycle were significantly increased in FATP1Tg. Thus, aconitase or alpha-keto-glutarate showed a 2 fold increase in 3 months old FATP1Tg. Moreover the global level of triglycerides was 80 fold higher in RPE and 5 fold higher in neural retina of 6 months old FATP1Tg. We also observed an increase of photoreceptor outer segments (up to 37%) and in the number of nuclei photoreceptors (up to 27%) confirmed by SD-OCT.
As expected by in-vitro studies, FATP1 seems to be able to slow the visual cycle in vivo. We note cumulative effects during aging of FATPTg with an increase of the global metabolism of RPE and a non-cell autonomous phenotype in photoreceptors. FATP1 might be a potential therapeutic tool for Stargardt disease where a selective decrease in the activity of RPE65 could slow the accumulation of lipofuscin, a photosensitive retinal waste deleterious for RPE.
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