Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE
| Autor: | Peters, Florian, Ebner, Lynn J A, Atac, David, Maggi, Jordi, Berger, Wolfgang, den Hollander, Anneke I, Grimm, Christian |
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| Přispěvatelé: | University of Zurich, Peters, Florian, Grimm, Christian |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
10018 Ophthalmology Clinic
11124 Institute of Medical Molecular Genetics 1503 Catalysis 1604 Inorganic Chemistry 1312 Molecular Biology 1706 Computer Science Applications 570 Life sciences biology 1607 Spectroscopy 610 Medicine & health 1606 Physical and Theoretical Chemistry Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] 1605 Organic Chemistry |
| Zdroj: | International Journal of Molecular Sciences, 23, 6 International Journal of Molecular Sciences, 23 |
| ISSN: | 1422-0067 |
| Popis: | Contains fulltext : 252024.pdf (Publisher’s version ) (Open Access) Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD. |
| Databáze: | OpenAIRE |
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