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Choroidal endothelial cells supply oxygen and nutrients to retinal pigment epithelial (RPE) cells and photoreceptors, recycle metabolites, and dispose of metabolic waste through the choroidal blood circulation. Death of the endothelial cells of the choroid may cause abnormal deposits including unesterified and esterified cholesterol beneath RPE cells and within Bruch's membrane that contribute to the progression of age-related macular degeneration (AMD), the most prevalent cause of blindness in older people. Translocator protein (TSPO) is a cholesterol-binding protein that is involved in mitochondrial cholesterol transport and other cellular functions. We have investigated the role of TSPO in choroidal endothelial cells. Immunocytochemistry showed that TSPO was localized to the mitochondria of choroidal endothelial cells. Choroidal endothelial cells exposed to TSPO ligands (Etifoxine or XBD-173) had significantly increased cholesterol efflux, higher expression of cholesterol homeostasis genes (LXRα, CYP27A1, CYP46A1, ABCA1 and ABCG1), and reduced biosynthesis of cholesterol and phospholipids from [14C]acetate, when compared to untreated controls. Treatment with TSPO ligands also resulted in reduced production of reactive oxygen species (ROS), increased antioxidant capacity, and reduced release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and VEGF) induced by oxidized LDL. These data suggest TSPO ligands may offer promise for the treatment of AMD.

Original publication

DOI

10.3390/ijms19123740

Type

Journal article

Journal

Int J Mol Sci

Publication Date

24/11/2018

Volume

19

Keywords

TSPO, age-related macular degeneration, cholesterol efflux, choroidal endothelial cells, inflammation, oxidative stress, ATP Binding Cassette Transporter 1, ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Biological Transport, Cell Line, Cholesterol, Choroid, Cytochrome P-450 Enzyme System, Endothelial Cells, Gene Expression Regulation, Humans, Interleukin-1beta, Ligands, Lipoproteins, LDL, Liver X Receptors, Macaca mulatta, Mitochondria, Oxazines, Oxidative Stress, Phospholipids, Purines, Reactive Oxygen Species, Receptors, GABA-A, Signal Transduction, Vascular Endothelial Growth Factor A