Laboratory for Retinal Cell Biology, Department of Ophthalmology, University Hospital Zurich, University of Zurich, 8952 Zurich, Switzerland.
Institute of Medical Molecular Genetics, University of Zurich, 8952 Zurich, Switzerland.
Int J Mol Sci. 2022 Mar 16;23(6):3194. doi: 10.3390/ijms23063194.
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 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 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in 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 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD.
年龄相关性黄斑变性（AMD）是一种黄斑区进行性疾病，其特征为视网膜色素上皮（RPE）萎缩和光感受器变性，导致老年人群在晚期严重视力丧失。胆固醇逆转运（RCT）受损以及 RPE 内的细胞内脂质积累与 AMD 的发病机制有关。在这里，我们重点关注 ATP 结合盒转运蛋白 A1（ABCA1），它是 RPE 中的主要胆固醇转运蛋白，并分析导致诱导多能干细胞（iPSC）衍生的 RPE 细胞（iRPE）中 ABCA1 失调的条件。我们的结果表明，位于 上的风险相关等位基因 rs1883025（C）和 rs2740488（A）与 ABCA1 mRNA 和蛋白水平升高以及 RPE 中胆固醇外排效率降低有关。AMD 的环境风险因素缺氧会降低 表达并增加细胞内脂质积累。肝 X 受体（LXR）激动剂的治疗会导致 表达增加和脂质积累减少。我们的数据加强了胆固醇外排在 RPE 中的稳态作用，并表明通过刺激 表达增加细胞内胆固醇外排可能会减轻脂质负荷，改善 RPE 存活并降低 AMD 的发病风险。
