Biswas Lincoln, Zhou Xinzhi, Dhillon Baljean, Graham Annette, Shu Xinhua
Department of Life Sciences, Glasgow Caledonian University, Glasgow G4?0BA, UK.
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16?4SB, UK.
Hum Mol Genet. 2017 Nov 15;26(22):4327-4339. doi: 10.1093/hmg/ddx319.
Cholesterol accumulation beneath the retinal pigment epithelium (RPE) cells is supposed to contribute the pathogenesis of age-related macular degeneration (AMD). Cholesterol efflux genes (APOE and ABCA1) were identified as risk factors for AMD, although how cholesterol efflux influences accumulation of this lipid in sub-RPE deposits remains elusive. The 18 kDa translocator protein, TSPO, is a cholesterol-binding protein implicated in mitochondrial cholesterol transport. Here, we investigate the function of TSPO in cholesterol efflux from the RPE cells. We demonstrate in RPE cells that TSPO specific ligands promoted cholesterol efflux to acceptor (apo)lipoprotein and human serum, while loss of TSPO resulted in impaired cholesterol efflux. TSPO-/- RPE cells also had significantly increased production of reactive oxygen species (ROS) and upregulated expression of proinflammatory cytokines (IL-1β and TNFα). Cholesterol (oxidized LDL) uptake and accumulation were markedly increased in TSPO-/- RPE cells. Finally, in aged RPE cells, TSPO expression was reduced and cholesterol efflux impaired. These findings provide a new pharmacological concept to treat early AMD patients by stimulating cellular cholesterol removal with TSPO specific ligands or by overexpression of TSPO in RPE cells.
视网膜色素上皮（RPE）细胞下的胆固醇积累被认为与年龄相关性黄斑变性（AMD）的发病机制有关。胆固醇流出基因（APOE和ABCA1）被确定为AMD的危险因素，尽管胆固醇流出如何影响这种脂质在RPE下沉积物中的积累仍不清楚。18 kDa转位蛋白TSPO是一种与线粒体胆固醇转运有关的胆固醇结合蛋白。在这里，我们研究TSPO在RPE细胞胆固醇流出中的功能。我们在RPE细胞中证明，TSPO特异性配体促进胆固醇向受体（载脂蛋白）和人血清的流出，而TSPO的缺失导致胆固醇流出受损。TSPO-/- RPE细胞的活性氧（ROS）产生也显著增加，促炎细胞因子（IL-1β和TNFα）的表达上调。TSPO-/- RPE细胞中胆固醇（氧化低密度脂蛋白）的摄取和积累明显增加。最后，在衰老的RPE细胞中，TSPO表达降低，胆固醇流出受损。这些发现为通过用TSPO特异性配体刺激细胞胆固醇清除或在RPE细胞中过表达TSPO来治疗早期AMD患者提供了一个新的药理学概念。
