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Goldis Malek, Mayur Choudhary, Edwin Meade, Erik Nelson, Donald McDonnell; Liver X Receptor signaling pathways and age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3458.
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Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. The early dry sub-type is characterized by accumulation of cholesterol-rich deposits below the retinal pigment epithelium (sub-RPE). Recent studies have identified several genes associated with AMD risk, in the high-density lipoprotein cholesterol pathway, including the ATP binding cassette transporter 1 (ABCA1). Liver X receptors (LXRs) are nuclear receptors that act as cholesterol sensors regulating not only lipid-metabolism and genes associated with reverse cholesterol transport including ABCA1, but also inflammation. Given the importance of lipid metabolism and inflammation in the pathogenesis of early dry AMD, we investigated the impact of LXR activation in RPE and choroidal endothelial cells, cells affected in AMD, and examined the eye phenotype of aged LXR double knockout mice.
LXR expression and activity were determined in ARPE19 and RF/6A endothelial cells treated with endogenous lipids, synthetic agonists and antagonists of the receptor using qPCR, western blot and luciferase assays. Expression of inflammatory and lipid-processing genes were measured in cells following treatment with agonists and antagonists and following knockdown of the receptor. In vivo examination of LXR knockout mice included evaluating the morphology of retina/RPE/choroid and histochemical staining for lipids.
We found that the LXRs are present and the signaling pathway can be activated using synthetic agonists in human RPE and endothelial cells. Inflammatory genes including MCP-1, TLR3 and 4 and lipid processing genes ABCA1 and SREBP are regulated by LXR. In vivo, the absence of LXR in 9 month old mice resulted in accumulation of lipid-rich, oil red o positive, sub-RPE deposits underlying approximately 80% the length of the RPE, along with lipid droplets within the RPE and Bruch’s membrane.
These findings support the physiological importance of LXR in lipid metabolism and inflammation in the RPE and choroidal endothelial cells and indicate that the LXR signaling pathway may be a potential therapeutic target against cholesterol-rich deposit formation.
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