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Wanwisa Promsote, Rajalakshmi Veeranan-Karmegam, Sudha Ananth, Vadivel Ganapathy, Pamela Martin; Regulation of the cholesterol efflux transporter ABCA1 by the niacin receptor GPR109A: potential relevance to drusen biogenesis and inflammation in age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2013;54(15):1379.
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Cholesterol is essential to maintenance of normal retinal structure and function, but is detrimental in excess. Retinal pigment epithelial (RPE) cells, cells central to AMD pathology, play a key role in lipid metabolism and management of retinal cholesterol. Interestingly however, little is known regarding the mechanisms involved. Here we evaluate the expression and localization of the cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) in RPE, and determine whether activation of the anti-inflammatory and anti-lipolytic receptor GPR109A has any influence thereon.
The expression and localization of ABCA1 was analyzed in wildtype (Gpr109a +/+) and Gpr109a-/- mouse retina using qPCR, western blot and immunofluorescent techniques. The influence of GPR109A activation on ABCA1 expression was evaluated in ARPE-19 and primary mouse RPE cells isolated from wildtype and Gpr109a-/- mouse retinas. Parallel experiments conducted using THP-1, human macrophage, cells served as positive controls. Additionally, cholesterol was measured in serum, RPE/eyecup and neural retina samples obtained from wildtype and Gpr109a-/- mice using a commercial assay kit (Cell Biolabs, Inc.).
ABCA1 protein localizes to both apical and basolateral membranes of RPE. ABCA1 mRNA and protein was significantly reduced in Gpr109a-/- mouse retina and primary RPE cells isolated from these animals. Furthermore, activation of GPR109A using GPR109A-specific ligands enhanced ABCA1 expression in ARPE-19 and Gpr109a+/+ primary RPE.
This is the first report on the specific localization of ABCA1 in RPE and on its coordinate regulation by GPR109A. Cholesterol is a major component of drusen and, it is pro-inflammatory. Novel strategies to reduce the accumulation of cholesterol beneath RPE and consequently, the number and size of drusen and resultant inflammation in aged eyes are sorely needed. Targeting of GPR109A/ABCA1 may represent one such strategy, and is therefore worthy of further investigation.
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