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Elodie AY Masson, Elise Léger-Charnay, Ségolène Gambert, Lucy Martine, Bénédicte Buteau, Marie-Annick Maire, Vincent Gigot, Alain M Bron, Catherine Creuzot-Garcher, Niyazi Acar, Lionel Bretillon; Characterization of cholesterol metabolism in an experimental model of glaucoma in rats. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5665. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is a neurodegenerative pathology characterized by retinal ganglion cell death. Cholesterol homeostasis disruption has been implicated in several neurodegenerative diseases such as Alzheimer and Huntington. However, its specific role in the retina and association with glaucoma remain unclear. The aim of this study was to characterize the modifications of cholesterol metabolism occurring during an experimental model of glaucoma in rats.
Eight-weeks old male rats were subjected to laser photocoagulation of episcleral veins, limbus and trabecular meshwork to elevate intraocular pressure. At a short (3 days) and a long (2 months) time period post-laser, the retinal levels of sterols and oxysterols were measured by gas chromatography. The expression of various genes implicated in cholesterol metabolism was assayed by RT-qPCR. Statistical significance was calculated using the paired Wilcoxon test (n=8).
At 3 days post-laser, the levels of cholesterol precursors, desmosterol and lathosterol, were strongly increased (x1.6 between laser-treated and contralateral retinas, p=0.008 and x3, p=0.02, respectively) while cholesterol levels were slightly increased (x 1.3, p=0.008). We did not detect any change in the levels of 24S-hydroxycholesterol, a major elimination form of cholesterol in retinal ganglion cells. On the contrary, the expression of ABCA1, a transporter regulating cholesterol efflux, as well as LXR, a transcription factor activating hypocholesterolemic pathways, was increased. The expression of LDL receptor, regulating cholesterol uptake, as well as SREBP2, a transcription factor activating hypercholesterolemic pathways, was decreased. At 2 months post-laser, cholesterol precursor levels were decreased. Interestingly, we also measured a significant increase in the expression of CYP27A1 (x1.8, p=0.02), an enzyme implicated in cholesterol efflux and in the levels of its product 27-hydroxycholesterol (x1.6, p=0.02).
Our observations suggest that cholesterol metabolism disturbances are associated with glaucoma. Indeed, hypocholesterolemic mechanisms are induced in the rat glaucoma model in order to counteract the activation of cholesterol biosynthetic pathways consecutive to intraocular pressure elevation. Moreover, our results suggest that CYP27A1 might play an important role in the regulation of cholesterol metabolism in the retina.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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