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Sandra S Hammer, Julia V Busik, Maria B Grant; THE ROLE OF THE SIRT1/LXR SIGNALING AXIS IN RETINAL ENDOTHELIAL CELL INFLAMMATION AND METABOLISM.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2728. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Liver x receptors (LXRs) are hypothesized to serve as a link between lipid metabolism and inflammation by promoting cholesterol efflux as well as exhibiting anti-inflammatory properties. NAD-dependent deacetylase SIRT1 is known to promote insulin secretion, reduce glucose tolerance and to play a critical role in regulating inflammation. SIRT1 has also been shown to interact with LXR to promote LXR activation. Additionally, previous literature has shown that starvation increases SIRT1 levels in mice. The purpose of this study was to investigate the role of SIRT1-LXR activation in control of inflammation and subsequent metabolic changes in retinal endothelial cells.
Bovine retinal endothelial cells (BRECs) were isolated and validated according to a previously published protocol. BRECs were treated with diabetic relevant stimulus TNFα (10ng/ml); LXR activator, DMHCA (1uM); or SIRT1 activator, SRT1720 (1uM). In order to model calorie restriction in vitro BRECs were serum starved (0% FBS) for 24hrs.SIRT1, IL1β, ABCA1 and ABCG1 were analyzed by qRT-PCR. Sirt1 activity was measured via histone deacetylase activity (HDAC) assay. LXR acetylation was measured via western blot analysis.
Treatment with pro-inflammatory cytokine, TNFα (10ng/ml) for 24hrs significantly increased cholesterol levels (p=0.0233, n=6), IL1β expression (p=0.334, n=8), IL6 (p<0.001, n=3) expression and resulted in decreased levels of HDAC activity (p=0.0123, n=3) in BRECs. Activation of LXR (DMHCA; p=0.0178, n=8) or SIRT1 (SRT1720; p=0.0084, n=6) prevented TNFα-induced inflammation. Serum starvation resulted in a significant increase in HDAC activity (p=0.0005, n=6) and SIRT1 (p=0.0063, n=3) expression levels. Lastly, serum starvation caused a decrease in LXR acetylated levels in BRECs.
The results of this study demonstrate that serum starvation promotes activation of the SIRT1-LXR pathway metabolism in retinal endothelial cells. Therefore, this study suggests that therapeutic fasting may serve to activate the SIRT1-LXR pathway providing the dual benefits of decreasing inflammation and promoting cholesterol metabolism in the retina.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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