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Sandra Hammer, Todd Lydic, Qi Wang, Sugata Hazra, Goldis Malek, Michael E Boulton, Maria B Grant, Julia V Busik; Downregulation of the SIRT1 and Liver X Receptor α/β signaling axis promotes diabetic retinopathy pathogenesis. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4248.
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Clinical trials have demonstrated a strong association between dyslipidemia and the progression of diabetic retinopathy (DR). Activation of LXRα/β prevents diabetes-induced retinal vascular damage. Moreover, SIRT1-mediated LXR activation has been shown to be beneficial in non-retinal systems, but the involvement of this signaling axis in DR remains unknown. The goal of this project was to investigate the role that the SIRT1-LXR signaling cascade plays in the progression of DR.
Bovine retinal endothelial cells (BRECs) were isolated and validated according to a previously published protocol. Human retinal endothelial cells (HRECs) were isolated from control or diabetic patients. BRECs and HRECs were treated with TNFα (10ng) for 24hrs. DMHCA (1ug) was used as a LXR activator. LXRα/β, SIRT1, CYP46A1, -27A1, -11A1, ABCA1 and -G1 were analyzed by qRT-PCR. Oxysterols and cholesterol esters were measured by high resolution/accurate mass LC-MS and direct infusion MS, respectively, on an Orbitrap Velos mass spectrometer. db/db diabetic mice were used to model diabetic retinopathy in vivo.
HRECs isolated from diabetic donors had significantly lower expression levels of LXRα/β and SIRT1 when compared to non-diabetic donors (n=6; p<0.01). Additionally, LXRα was significantly decreased in BRECs and control HRECs treated with TNFα (10ng/ml) (n=9, n=3; p<0.01, respectively). Cholesterol metabolizing enzymes, CYP46A1 and -11A1 were significantly increased after TNFα treatment (n=9; p<0.05) in BREC while CYP46A1, -27A1 and -11A1 were downregulated in control HRECs after TNFα treatment (n=3; p<0.01). LXR activation (DMHCA) prevented TNFα-induced ABCA1 and -G1 downregulation (n=9; p<0.05). Oxysterol levels were decreased (n=9; p<0.05) and total retinal cholesterol ester abundance was increased in diabetic animals compared to control animals. Lastly, retinal levels of SIRT1 and LXRα/β were downregulated in diabetic mice after 8 weeks of diabetes and LXR activation prevented development of acellular capillaries in db/db mice (n=6; p<0.05).
This study demonstrates the detrimental effect diabetes has on LXR and SIRT1 retinal levels. Activation of LXR prevents DR-induced pathology in diabetic animals. Hence, these studies suggest that retinal-specific activation of LXR has the potential to be a novel therapeutic target in the treatment of DR.
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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