Causal role of oxidative stress in unfolded protein response development in the hyperthyroid state

Abstract

L-3,3',5-Triiodothyronine (T-3) induced liver oxidative stress underlies significant protein oxidation, which may trigger the unfolded protein response (UPR). Administration of daily doses of 0.1 mg T-3 for three consecutive days significantly increased the rectal temperature of rats and liver O-2 consumption rate, with higher protein carbonyl and 8-isoprostane levels, glutathione depletion, and absence of morphological changes in liver parenchyma. Concomitantly, liver protein kinase RNA like endoplasmic reticulum (ER) kinase and eukaryotic translation initiator factor 2 alpha were phosphorylated in T-3 treated rats compared to controls, with increased protein levels of binding immunoglobulin protein and activating transcription factor 4. In addition, higher mRNA levels of C/EBP homologous protein, growth arrest and DNA damage 34, protein disulfide isomerase, and ER oxidorecluclin 1 alpha were observed, changes that were suppressed by N-acelyicysleine (0.5 g/kg) given before each close of T-3. In conclusion, T-3 induced liver oxidative stress involving higher protein oxidation status has a causal role in UPR development, a response that is aimed to alleviate ER stress and promote cell survival.