TSPO Ligands Promote Cholesterol Efflux and Suppress Oxidative Stress and Inflammation in Choroidal Endothelial Cells

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.

• Publication year

  2018

• Venue

  International Journal of Molecular Sciences

• Publication date

  2018-11-24

• Fields of study

  Biology, Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.3390/ijms19123740PMID 30477223PMCID 6321017
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• TSPO ligands reduce cholesterol and phospholipid biosynthesis and suppress oxidized LDL-induced oxidative stress and inflammation.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• TSPO ligands increase cholesterol efflux and cholesterol homeostasis gene expression in choroidal endothelial cells.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• TSPO localizes to mitochondria in choroidal endothelial cells.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review

• cholesterol and phospholipid biosynthesis

  metabolic process

  The acetate-derived lipid synthesis pathway measured by incorporation of [14C]acetate.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• cholesterol efflux

  cellular process

  The export of cholesterol from cells to extracellular acceptors.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• cholesterol homeostasis genes

  gene set

  Genes associated with intracellular cholesterol balance, including LXRα, CYP27A1, CYP46A1, ABCA1, and ABCG1.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• choroidal endothelial cells

  cell type

  Endothelial cells from the choroid that support the outer retina and participate in choroidal blood circulation.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• oxidative stress and inflammation

  biological process

  The combined oxidative and inflammatory response measured here through ROS production, antioxidant capacity, and cytokine release.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• oxidized ldl

  lipoprotein

  Oxidatively modified low-density lipoprotein used as a cellular stress stimulus in the experiments.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• tspo

  protein

  A cholesterol-binding translocator protein involved in mitochondrial cholesterol transport and other cellular functions.

  Aliases: translocator protein

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review
• tspo ligands

  compound

  Small molecules used in this work to bind TSPO, including Etifoxine and XBD-173.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) review

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