Coucha Maha, Mohamed Islam N, Elshaer Sally L, Mbata Osinakachuk, Bartasis Megan L, El-Remessy Azza B
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.
World J Diabetes. 2017 Feb 15;8(2):56-65. doi: 10.4239/wjd.v8.i2.56.
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 ( < 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 ( < 0.05). , 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 ( < 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.
阐明高糖饮食诱导的内质网应激如何上调Müller细胞中硫氧还蛋白相互作用蛋白的表达，从而导致视网膜炎症。
将雄性C57Bl/J小鼠分为正常饮食组和60%高脂饮食组，喂养4 - 8周。在为期4周的研究中，小鼠接受内质网应激抑制剂苯丁酸钠（PBA）治疗2周。通过口服葡萄糖耐量试验评估胰岛素抵抗情况。在视网膜Müller神经胶质细胞系以及从野生型和硫氧还蛋白相互作用蛋白基因敲除小鼠分离出的原代Müller细胞中，检测棕榈酸 - 牛血清白蛋白（BSA）（400μmol/L）的作用。测定硫氧还蛋白相互作用蛋白、内质网应激标志物、miR - 17 - 5p mRNA以及核苷酸结合寡聚化结构域样受体蛋白（NLRP3）和IL1β蛋白的表达。
8周高脂饮食诱导肥胖和胰岛素抵抗，表现为体重增加和葡萄糖耐量受损。通过定量实时聚合酶链反应，我们发现高脂饮食引发视网膜内质网应激标志物的表达（<0.05）。这些作用与硫氧还蛋白相互作用蛋白增加和miR - 17 - 5p表达降低有关，而通过用PBA抑制内质网应激可使其恢复（<0.05）。此外，棕榈酸 - BSA引发内质网应激标志物，同时伴有视网膜Müller神经胶质细胞系中miR - 17 - 5p降低和硫氧还蛋白相互作用蛋白mRNA诱导（<0.05）。棕榈酸上调从野生型分离出的原代Müller细胞中NLRP3和IL1β的表达。然而，使用从硫氧还蛋白相互作用蛋白基因敲除小鼠分离出的原代Müller细胞可消除棕榈酸介导的NLRP3和IL1β增加。
我们的研究表明，针对内质网应激或硫氧还蛋白相互作用蛋白是肥胖诱导的视网膜炎症早期干预的潜在治疗策略。
