Effect of a TSPO ligand on retinal pigment epithelial cholesterol homeostasis in high-fat fed mice, implication for age-related macular degeneration

• Published in: Experimental eye research 2021-07, Vol.208, p.108625-108625, Article 108625
• Main Authors: Biswas, Lincoln, Ibrahim, Khalid Subhi, Li, Xing, Zhou, Xinzhi, Zeng, Zhihong, Craft, John, Shu, Xinhua
• Format: Article
• Language: English
• Subjects: Age related macular degeneration; Cholesterol homeostasis; Etifoxine; Retinal pigment epithelial cells; TSPO ligand
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2021.108625

Age-related Macular Degeneration (AMD) is a major cause of sight impairment in the elderly with complex aetiology involving genetics and environment and with limited therapeutic options which have limited efficacy. We have previously shown in a mouse-model of the condition, induced by feeding a high fat diet, that adverse effects of the diet can be reversed by co-administration of the TSPO activator, etifoxine. We extend those observations showing improvements in retinal pigment epithelial (RPE) cells with decreased lipids and enhanced expression of cholesterol metabolism and transport enzymes. Further, etifoxine decreased levels of reactive oxygen species (ROS) in RPE and inflammatory cytokines in RPE and serum. With respect to gut microbiome, we found that organisms abundant in the high fat condition (e.g. in the genus Anaerotruncus and Oscillospira) and implicated in AMD, were much less abundant after etifoxine treatment. The changes in gut flora were associated with the predicted production of metabolites of benefit to the retina including tryptophan and other amino acids and taurine, an essential component of the retina necessary to counteract ROS. These novel observations strengthen earlier conclusions that the mechanisms behind improvements in etifoxine-induced retinal physiology involve an interaction between effects on the host and the gut microbiome. •Etifoxine treatment decreased cholesterol and other lipid levels in the RPE of high fat diet-fed mice.•Etifoxine enhanced expression of cholesterol homeostasis-associated genes.•Etifoxine attenuated inflammation in the RPE and serum of high fat diet fed mice.•Etifoxine regulated gut microbiota of high fat diet fed mice.•Etifoxine offers therapeutic potential for AMD patients.