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Norimitsu Ban, Abdoulaye Sene, Tae Jun Lee, Zhenyu Dong, Andrea Santeford, Jonathan Lin, Rajendra Apte; Photoreceptor Cholesterol Metabolism Regulates Age-Related Retinal Neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):977. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Cholesterol is an important structural component of cellular membranes and a precursor of steroid molecules, and thus tissue cholesterol level is tightly controlled in all tissues including the retina. Although coordinated regulation of de novo biosynthesis, uptake, and efflux regulate cholesterol level in tissues, the effect of disrupted cholesterol metabolism in the retina on its function and structure is largely unknown. This study assessed the effects of impaired cholesterol efflux in photoreceptors on retinal function and morphology.
We generated conditional knockout mice lacking both ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), which are responsible for cholesterol efflux, in rods (Abca1/Abcg1 flox/flox Rhod-iCre positive: Abca1/g1-rod/-rod) or cones (Abca/Abcg1 flox/flox HRGP-Cre positive: Abca1/g1-cone/-cone). Retinas were structurally evaluated by biomicroscopy, optical coherence tomography (OCT), histology and electron microscopy at 3-18 months of age. Cholesterol metabolites were analyzed by mass spectrometry. Retinal function was evaluated by electroretinography. In addition to normal diet, a cohort of knockout mice were also placed on a high fat diet.
At 3 months of age, Abca1/g1-rod/-rod did not show any functional and morphological phenotype compared to littermate controls (Abca1/g1F/F). At 12 months of age, Abca1/g1-rod/-rod showed age-related accumulation of cholesterol metabolites in retinal pigmented epithelium (RPE) and scotopic photoreceptor dysfunction. At 18 months of age, Abca1/g1-rod/-rod showed degenerated rod outer segments and both scotopic and photopic dysfunction. High fat diet accelerated these age-associated neuroretinal degeneration. On the other hand, Abca1/g1-cone/-cone did not show any phenotype during the observation period.
Impaired cholesterol efflux in rods, but not cones, result in lipid accumulation in RPE and age-associated neuroretinal degeneration. Targeted metabolic interventions that regulate cholesterol efflux and homeostasis in the neurosensory retina may provide potential therapeutic avenues and prevent vision loss.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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