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Kiana Wood, Sandra Hammer, Elahe Crockett, Maria B Grant, Julia V Busik; ACTIVATION OF THE SIRT1-LXR SIGNALLING PATHWAY IN RETINAL PIGMENTED EPITHELIAL CELLS PROMOTES CHOLESTEROL METBOLISM. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4039.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic Retinopathy (DR) is a sight threatening disease with few treatment options. Dyslipidemia has shown to play a significant role in the progression of DR. Liver X Receptors (LXRα/β) are known cholesterol metabolism regulators that also play a role in preventing pro-inflammatory genes upregulation. Retinal Pigmented Epithelial Cells (RPEs) are important in retinal cholesterol uptake and elimination. Additionally, RPE are one of the retinal cells heavily affected by DR. Knockdown of LXR in animals leads to increased retinal cholesterol levels when compared to controls. SIRT1 has recently been shown to activate LXR in non-retinal studies but the role of the SIRT1-LXR signaling axis in DR has not yet been studied.
Bovine retinal pigmented cells (BRPE) were treated with TNFα (10ng/ml), and the role of SIRT1-LXR signaling axis was examined using SIRT1 activator SIRT1720 (1µM) and LXR activator DMHCA (1µg/ml). LXRα/β, the ATP binding cassette transporters (ABCA1 and ABCG1), and cholesterol metabolizing enzymes (CYP27A1, CYP46A1, and CYP11A1) were analyzed using qRT-PCR. SIRT1-directed siRNA was used to inhibit SIRT1 expression levels.
LXRα, ABCA1 and ABCG1 mRNA levels decreased when BRPEs were treated with TNFα for 24hrs (p<0.01, n=6). The cholesterol metabolizing enzymes (CYP27A1, CYP46A1, and CYP11A1) were decreased when treated with TNFα (p<0.01, n=6). Furthermore, treatment with SIRT1 activator, SRT1720, for 24hrs prevented TNFα-induced ABCA1 and ABCG1 downregulation (p<0.001, n=9). LXR activator, DMHCA, prevented TNFα-induced ABCA1 and ABCG1 downregulation (p<0.01, n=3). Additionally, SIRT1 inhibition it decreased cholesterol metabolizing enzyme CYP11A1 and ABCA1 (p<0.05, n=3) while having no statistical effect on LXRα expression.
Inflammatory cytokine stimulation caused a decrease in retinal cholesterol metabolizing enzymes and transporter proteins. Activation of the SIRT1-LXR signaling axis prevented TNFα-induced downregulation of cholesterol metabolism in retinal cells. Taken together this work suggest that activation of the SIRT1-LXR pathway can help restore normal cholesterol metabolism in diabetic retina and prevent dyslipidemia-induced retinal pathology.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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