Published online Feb 15, 2017. doi: 10.4239/wjd.v8.i2.56
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
To elucidate how high diet-induced endoplasmic reticulum-stress upregulates thioredoxin interacting protein expression in Müller cells leading to retinal inflammation.
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.
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.
Our work suggests that targeting endoplasmic reticulum-stress or thioredoxin interacting protein are potential therapeutic strategies for early intervention of obesity-induced retinal inflammation.
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.