title: High fat diet dysregulates microRNA-17-5p and triggers retinal inflammation: Role of endoplasmic-reticulum-stress.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Our work suggests that targeting endoplasmic reticulum-stress or thioredoxin interacting protein are potential therapeutic strategies for early intervention of obesity-induced retinal inflammation.
authors.affiliation: 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.
authors.forename: Maha
authors.initials: M
authors.lastname: Coucha
authors.affiliation: 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.
authors.forename: Islam N
authors.initials: IN
authors.lastname: Mohamed
authors.affiliation: 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.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Elshaer
authors.affiliation: 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.
authors.forename: Osinakachuk
authors.initials: O
authors.lastname: Mbata
authors.affiliation: 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.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Bartasis
authors.affiliation: 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.
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
keywords: Endoplasmic-reticulum-stress; High fat diet; Inflammation; Micro-RNA 17-5p; Palmitate; Thioredoxin-interacting protein