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Mercedes Elizabeth Serratos, Sandra S Hammer, Delaney Marie McFarland, Elahé Crockett, Maria Grant, Julia V Busik; Activation of Liver X Receptor Reverses Decrease in Cholesterol Efflux in Diabetic Retinal Endothelial Cells.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3556. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Data from recent clinical trials suggest that dysregulation of cholesterol metabolism significantly contributes to the pathogenesis of diabetic retinopathy (DR), the number one cause of blindness among working age individuals worldwide. Liver X receptors (LXRα/LXRβ) are the central regulators of cholesterol elimination by activation of the reverse cholesterol transport (RCT) pathway. Specifically, LXRs have been shown to promote cholesterol efflux by activation of ATP-binding cassette transporters, ABCA1 and ABCG1. This study examines the role of LXR activation in control and diabetic human retinal endothelial cells (HREC).
HREC were isolated from diabetic and non-diabetic control donors. HREC were treated with tumor necrosis factor (TNFα) (10ng/ml), and/or LXR agonist dimethyl-3β-hydroxy-cholenamide (DMHCA) (1uM) for 24hrs. RNA was analyzed by real time-PCR for LXRα, ABCA1 and ABCG1. Cyclophilin A was used as a loading control. Western blot was performed on HREC for protein analysis. One-way ANOVA was used for statistical analysis.
LXRα was significantly downregulated in HREC isolated from diabetic donors compared to non-diabetic controls (n=3 donors per group, p<0.0057). Treatment of HREC with DMHCA significantly increased LXR signaling targets, ABCA1 and ABCG1. This increase was seen in the presence of pro-inflammatory cytokine TNFα stimulation (TNFα vs. TNFα+DMHCA, ABCA1: n=3, p=0.0031; ABCG1: n=3, p=0.0026) as well as in the presence of diabetes (diabetes vs. diabetes+DMHCA, ABCA1: n=3 p<0.0001; ABCG1: n=3, p<0.0001). TNFα significantly decreased ABCA1 total protein as well. LXR activation with DMHCA prevented TNFα-induced ABCA1 protein downregulation.
LXR agonists, such as DMHCA, effectively increase RCT genes in control, diabetic and cytokine-treated HREC. These data suggest that LXR agonists can be used as a strategy to normalize cholesterol metabolism in diabetic retina.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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