Deletion of TSPO Causes Dysregulation of Cholesterol Metabolism in Mouse Retina

Abstract

Cholesterol dysregulation has been implicated in age-related macular degeneration (AMD), the most common cause of visual impairment in the elderly. The 18 KDa translocator protein (TSPO) is a mitochondrial outer membrane protein responsible for transporting cholesterol from the mitochondrial outer membrane to the inner membrane. TSPO is highly expressed in retinal pigment epithelial (RPE) cells, and TSPO ligands have shown therapeutic potential for the treatment of AMD. Here, we characterized retinal pathology of Tspo knockout (KO) mice using histological, immunohistochemical, biochemical and molecular biological approaches. We found that Tspo KO mice had normal retinal morphology (by light microscopy) but showed elevated levels of cholesterol, triglycerides and phospholipids with perturbed cholesterol efflux in the RPE cells of Tspo KO mice. Expression of cholesterol-associated genes (Nr1h3, Abca1, Abcg1, Cyp27a1 and Cyp46a1) was significantly downregulated, and production of pro-inflammatory cytokines was markedly increased in Tspo KO retinas. Furthermore, microglial activation was also observed in Tspo KO mouse retinas. These findings provide new insights into the function of TSPO in the retina and may aid in the design of new therapeutic strategies for the treatment of AMD.

Chinese medicine, Qijudihuang pill, mediates cholesterol metabolism and regulates gut microbiota in high-fat diet-fed mice, implications for age-related macular degeneration

“…Knockout of cholesterol efflux-related genes (e.g., Apoe and Abca1 ) and cholesterol metabolism genes such as Cyp27a1 and Cyp46a1 cause retinal pathology in mice ( 11 – 14 ). We also found that the translocator protein, TSPO, mediated RPE cholesterol efflux, and loss of TSPO caused intracellular accumulation of cholesterol in human and mouse RPE cells ( 15 , 16 ). High intake of dietary cholesterol has been reported to be associated with an increase in the risk of developing AMD ( 17 – 19 ).…”

Cholesterol metabolism: physiological regulation and diseases

“…201 Some studies have shown that the activation of TSPO in mice leads to an increase in cholesterol efflux from RPE cells, a decrease in the levels of lipids (cholesterol, triglycerides, and phospholipids) in the retina, an increase in the expression of cholesterol-related genes (LXR, ABCA1/ABCG1, and ApoE) and the inhibition of inflammation. 166,[202][203][204] Simultaneously, TSPO can regulate the activity of STARD1, 205 but the relationship between TSPO and STARD3 remains unknown. We previously reported that LXR plays a crucial role in cholesterol efflux by activating ABCA1 and ABCG1 to increase cholesterol efflux and inhibit inflammation.…”

“…TSPO combines with other proteins, such as STARD1 and VDAC, forming a multiprotein complex responsible for cholesterol transport 201 . Some studies have shown that the activation of TSPO in mice leads to an increase in cholesterol efflux from RPE cells, a decrease in the levels of lipids (cholesterol, triglycerides, and phospholipids) in the retina, an increase in the expression of cholesterol‐related genes (LXR, ABCA1/ABCG1, and ApoE) and the inhibition of inflammation 166,202–204 . Simultaneously, TSPO can regulate the activity of STARD1, 205 but the relationship between TSPO and STARD3 remains unknown.…”

Bottlenecks in the Investigation of Retinal Sterol Homeostasis

“…The predominant hydroxy- and oxysterols generated by CYP27A1 and CYP46A1 include 24-, 25-, and 27-OH-cholesterol [ 77 ]. Other enzymatic players involved in generating oxysterols are TSPO (translocator protein) and NADPH oxidases [ 78 ]. Cellular stressors such as Fenton reaction products can also contribute to the generation of oxysterols [ 79 ].…”