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Maha Coucha, Islam N Mohamed, Megan L. Bartasis, Azza B El-Remessy; High fat diet dysregulates microRNA-17-5p and enhances retinal TXNIP expression: Role of ER-stress. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2391.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously shown that high fat diet (HFD) induced retinal expression of thioredoxin interacting protein (TXNIP), a regulator of the antioxidant thioredoxin. Deletion of TXNIP prevented HFD-induced activation of NLRP3-inflammasome and retinal vascular dysfunction. Prior studies showed that the small non coding RNA miR-17-5p is destabilized by endoplasmic reticulum (ER) stress. The aim of this study is to elucidate how HFD dysregulates miR17-5p and upregulates TXNIP expression in vivo and in vitro.
Male C57Bl/J mice were kept either on normal diet (ND) or 60% HFD for 4-8 weeks. Insulin resistance was assessed by oral glucose tolerance before sacrifice. Effects of palmitate-BSA (400µM) were examined in rMC-1 Muller cells and retinal endothelial cells. Expression of TXNIP, ER-stress markers and miR-17-5p mRNA was determined.
HFD induced obesity and insulin resistance assessed by increases in body weight and impaired glucose tolerance. HFD induced expression of retinal ER-stress markers including the CHOP, ATF6 and the RNAse IREα, compared to normal diet (P<0.05). These effects were associated with significant increases in TXNIP expression and decreases in miR-17-5p expression compared to ND (p<0.05). In vitro, palmitate-BSA significantly (p<0.05) reduced miR-17-5p and induced TXNIP mRNA in both endothelial and Muller cells. Tunicamycin (ER-stress inducer, 5µg/ml) reduced miR-17-5p and increased TXNIP mRNA, which were mitigated by prior treatment with IREα inhibitor.
HFD induced retinal ER-stress markers, dysregulated miR-17-5p and upregulated TXNIP expression. Our work suggests that modulators of ER-stress and microRNA mimics will be potential therapeutic strategies for early intervention of obesity-induced retinal microvascular abnormalities.
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