Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Feb 15, 2017; 8(2): 56-65
Published online Feb 15, 2017. doi: 10.4239/wjd.v8.i2.56
High fat diet dysregulates microRNA-17-5p and triggers retinal inflammation: Role of endoplasmic-reticulum-stress
Maha Coucha, Islam N Mohamed, Sally L Elshaer, Osinakachuk Mbata, Megan L Bartasis, Azza B El-Remessy
Maha Coucha, Islam N Mohamed, Sally L Elshaer, Osinakachuk Mbata, Megan L Bartasis, Azza B El-Remessy, Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912, United States
Author contributions: All the authors contributed to the manuscript.
Institutional review board statement: The study was reviewed and approved by the Charlie Norwood VA Medical Center Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Association for Research in Vision and Ophthalmology statement for use of animals in ophthalmic and vision research, and Charlie Norwood VA Medical Center Animal Care and Use Committee (ACORP#15-04-080).
Conflict-of-interest statement: There is no conflict of interest.
Data sharing statement: Data will be available upon request.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Azza El-Remessy, PhD, RPh, FAHA, Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, 114 Academic Building, Augusta, GA 30912, United States. aelremessy@outlook.com
Telephone: +1-706-7330188 Fax: +1-706-8232268
Received: September 2, 2016
Peer-review started: September 6, 2016
First decision: September 29, 2016
Revised: October 22, 2016
Accepted: December 13, 2016
Article in press: December 14, 2016
Published online: February 15, 2017
Processing time: 166 Days and 8.2 Hours
Abstract
AIM

To elucidate how high diet-induced endoplasmic reticulum-stress upregulates thioredoxin interacting protein expression in Müller cells leading to retinal inflammation.

METHODS

Male C57Bl/J mice were fed either normal diet or 60% high fat diet for 4-8 wk. During the 4 wk study, mice received phenyl-butyric acid (PBA); endoplasmic reticulum-stress inhibitor; for 2 wk. Insulin resistance was assessed by oral glucose tolerance. Effects of palmitate-bovine serum albumin (BSA) (400 μmol/L) were examined in retinal Müller glial cell line and primary Müller cells isolated from wild type and thioredoxin interacting protein knock-out mice. Expression of thioredoxin interacting protein, endoplasmic reticulum-stress markers, miR-17-5p mRNA, as well as nucleotide-binding oligomerization domain-like receptor protein (NLRP3) and IL1β protein was determined.

RESULTS

High fat diet for 8 wk induced obesity and insulin resistance evident by increases in body weight and impaired glucose tolerance. By performing quantitative real-time polymerase chain reaction, we found that high fat diet triggered the expression of retinal endoplasmic reticulum-stress markers (P < 0.05). These effects were associated with increased thioredoxin interacting protein and decreased miR-17-5p expression, which were restored by inhibiting endoplasmic reticulum-stress with PBA (P < 0.05). In vitro, palmitate-BSA triggered endoplasmic reticulum-stress markers, which was accompanied with reduced miR-17-5p and induced thioredoxin interacting protein mRNA in retinal Müller glial cell line (P < 0.05). Palmitate upregulated NLRP3 and IL1β expression in primary Müller cells isolated from wild type. However, using primary Müller cells isolated from thioredoxin interacting protein knock-out mice abolished palmitate-mediated increase in NLRP3 and IL1β.

CONCLUSION

Our work suggests that targeting endoplasmic reticulum-stress or thioredoxin interacting protein are potential therapeutic strategies for early intervention of obesity-induced retinal inflammation.

Keywords: High fat diet; Palmitate; Endoplasmic-reticulum-stress; Inflammation; Thioredoxin-interacting protein; Micro-RNA 17-5p

Core tip: We previously showed that high fat diets (HFD) induced retinal inflammation and vascular dysfunction. These results were associated with an increase in thioredoxin interacting protein (TXNIP) at the mRNA and protein level. Here, we examined the mechanisms by which HFD triggers retinal TXNIP. Interestingly, we found that HFD/palmitate triggers ER-stress mediators including the inositol requiring enzyme 1, an RNAse that can degrade number of mRNAs including the microRNA; miR-17-5p and sustains TXNIP expression. Inhibiting ER-stress prevented the increase in TXNIP in vivo and in Müller cells, the main glia in the retina. Deletion of TXNIP blunted NLRP-3 inflammasome and IL-1β release in Müller cells.