Retinal pigment epithelium cholesterol efflux mediated by the 18kDa translocator protein, TSPO, a potential target for treating age-related macular degeneration

Lincoln Biswas, Xinzhi Zhou, Baljean Dhillon, Annette Graham, Xinhua Shu*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

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 18kDa 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 promote 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-1ß and TNFa). 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.
Original languageEnglish
Pages (from-to)4327–4339
Number of pages13
JournalHuman Molecular Genetics
Volume26
Issue number22
Early online date24 Aug 2017
DOIs
Publication statusPublished - 15 Nov 2017

Keywords

  • TSPO, cholesterol efflux, retinal pigment epithelium cell (RPE), age-related macular degeneration

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