TSPO ligands promote cholesterol efflux and suppress oxidative stress and inflammation in choroidal endothelial cells

Lincoln Biswas, Fahad Farhan, James Reilly, Christopher Bartholomew, Xinhua Shu

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)
150 Downloads (Pure)

Abstract

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 languageEnglish
Article number3740
JournalInternational Journal of Molecular Sciences
Volume19
Issue number12
Early online date24 Nov 2018
DOIs
Publication statusPublished - Dec 2018

Keywords

  • TSPO
  • choroidal endothelial cells
  • oxidative stress
  • age-related macular degeneration
  • inflammation
  • cholesterol efflux
  • phospholipids/antagonists & inhibitors
  • cytochrome P-450 enzyme system/genetics
  • humans
  • purines/pharmacology
  • biological transport/drug effects
  • ATP binding cassette transporter, subfamily G, member 1/genetics
  • macaca mulatta
  • endothelial cells/cytology
  • oxazines/pharmacology
  • oxidative stress/drug effects
  • lipoproteins, LDL/antagonists & inhibitors
  • mitochondria/drug effects
  • liver X receptors/genetics
  • receptors, GABA-A/genetics
  • cell line
  • signal transduction
  • cholesterol/metabolism
  • gene expression regulation
  • reactive oxygen species/antagonists & inhibitors
  • animals
  • interleukin-1beta/antagonists & inhibitors
  • ligands
  • ATP binding cassette transporter 1/genetics
  • vascular endothelial growth Factor A/antagonists & inhibitors
  • choroid/cytology

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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