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Goldis Malek, Amanda Bednar, Peng Hu; Aryl Hydrocabron Receptor (AhR) Activation Regulates Lipid Synthesis in Retinal Pigment Epithelial (RPE) Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4291.
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© ARVO (1962-2015); The Authors (2016-present)
AhR is a nuclear receptor activated by environmental contaminants such as dioxin and benzo(a)pyrene. These toxins have been shown to promote the development of atherosclerosis-related cardiovascular disease and lipid accumulation in macrophages. Previously we demonstrated that the AhR signaling pathway is activated in human RPE cells after treatment with cigarette smoke extract and dioxin. Given that cigarette smoking is an established risk factor for age-related macular degeneration, we investigated the molecular mechanisms underlying AhR activation in RPE cells.
Expression of AhR-regulated genes in dioxin and cigarette smoke extract treated ARPE19 cells transfected with and without AhR siRNA was determined through microarray and quantitative real-time PCR. Gene pathways were clustered using GoRilla. The effect of cholesterol on AhR activation was evaluated using luciferase based activity assays, qPCR and Western blot analysis. Cellular lipid content was determined based on oil red staining and cholesterol/cholesterol ester quantitation assays.
Microarray analysis revealed increased expression of genes involved in lipid metabolism in ARPE19 cells, after exposure to dioxin and regulated through AhR. These included but are not limited to CYP2J2, ABCA1, FADS, PPARdelta and LDLR. Treatment with cholesterol and 25 hydroxy cholesterol activated AhR and stimulated expression of AhR specific phase I toxin-metabolizing genes CYP1A1, CYP1B1, IL1-B and AhRR. Dioxin triggered lipid accumulation in cells.
Environmental toxins regulate lipid metabolism and accumulation in RPE cells through the AhR. Cholesterol and 25 hydroxy cholesterol, which is formed after a dietary meal from endogenous cholesterol, are activating ligands of AhR. Activation of the AhR signaling pathway may play a role in pathogenic accumulation of the lipid-protein rich deposits under the RPE in aging and characteristic of dry age-related macular degeneration.
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