title: Causal role of oxidative stress in unfolded protein response development in the hyperthyroid state.
abstract: L-3,3',5-Triiodothyronine (T3)-induced liver oxidative stress underlies significant protein oxidation, which may trigger the unfolded protein response (UPR). Administration of daily doses of 0.1mg T3 for three consecutive days significantly increased the rectal temperature of rats and liver O2 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 2α were phosphorylated in T3-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 oxidoreductin 1α were observed, changes that were suppressed by N-acetylcysteine (0.5 g/kg) given before each dose of T3. In conclusion, T3-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.
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile. Electronic address: lvidela@med.uchile.cl.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Videla
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile.
authors.forename: Virginia
authors.initials: V
authors.lastname: Fernández
authors.affiliation: School of Medical Technology, Faculty of Health and Odontology, Diego Portales University, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Cornejo
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile.
authors.forename: Romina
authors.initials: R
authors.lastname: Vargas
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile.
authors.forename: Juan
authors.initials: J
authors.lastname: Carrasco
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile; Department of Medical Technology, Faculty of Medicine, University of Chile, Santiago-7, Chile.
authors.forename: Nelson
authors.initials: N
authors.lastname: Varela
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006980:Hyperthyroidism / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000633:toxicity*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D014284:Triiodothyronine; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D005978:Glutathione; D000111:Acetylcysteine
keywords: Free radicals; Liver oxidative stress; N-acetylcysteine; Protein oxidation; Thyroid hormone calorigenesis; Unfolded protein response