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Bhanu C. Dasari, Othman Ghribi; The oxysterol, 27-hydroxycholesterol, disrupts Estrogen Receptor and Liver X Receptor signaling in Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6487.
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We demonstrated that the cholesterol oxidation product 27-hydroxycholesterol (27-OHC) triggers pathological hallmarks relevant to both Alzheimer’s disease (AD) and Age Related Macular Degeneration (AMD) in retinal pigment epithelial cells. 27-OHC is an endogenous ligand of liver X receptors (LXR) and also is a selective estrogen receptor modulator. Both Estrogen receptors (ERs) and LXRs are suggested to be implicated in AMD development. The purpose of our study was to determine the extent to which LXRs and ERs are involved in 27-OHC-induced AD and AMD like pathological hallmarks.
ARPE-19 cells were grown until confluency for all experiments. Estrogen responsive element and LXR responsive element transfections and Dual Luciferase Assays were carried out for measuring transcriptional activities of ER and LXR. Cytotoxicity, mitochondrial membrane potential, and reactive oxygen species were determined with LDH, JC-1 and DCFH-DA assays respectively. Changes in ERs and LXRs levels were determined with western blotting.
Retinal pigment epithelial cells express LXRs and ERs and are transcriptionally active. While 27-OHC induces LXR-mediated transcriptional activity, it inhibits ER-mediated transcriptional activity. Treatment with ER agonist estradiol (E2) and LXR antagonist ECHS protected cells from 27-OHC induced cytotoxicity.
Increased 27-OHC levels following hypercholesterolemia can inhibit ERs abrogating the protective effects of estrogen and activate LXR signaling causing cell dysfunction. By disturbing both LXR and ER signaling, 27-OHC might play role in the development of AMD.
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