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

doi:10.1016/j.freeradbiomed.2015.09.004

Free Radical Biology and Medicine

Volume 89, December 2015, Pages 401-408

https://doi.org/10.1016/j.freeradbiomed.2015.09.004 Get rights and content

Highlights

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T₃-induced oxidative stress triggers substantial protein oxidation in the liver.
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T₃-dependent protein oxidation associates with the liver unfolded protein response (UPR).
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Induction of UPR by T₃ involves the PERK regulatory axis and PDI/ERO1α upregulation.
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Liver enhancement of UPR components by T₃ is suppressed by N-acetylcysteine.
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Oxidative stress has a causal role in UPR expansion aiming to promote cell survival.

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 0.1 mg 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.

Graphical abstract

Section snippets

Animal treatment

Male Sprague–Dawley rats (animal facility of the Institute of Biomedical Sciences, Faculty of Medicine, University of Chile) weighing 180–200 g were housed on a 12 h light/dark cycle and were provided with rat chow and water ad libitum. Animals received an intraperitoneal dose of 0.1 mg of T₃/kg bw or equivalent volumes of hormone vehicle (0.1 N NaOH, controls) at time 0, 24, and 48 h, and studies were performed 24 h after hormone treatment. At this experimental time, T₃-induced calorigenesis was

T₃-induced calorigenesis is associated with liver oxidative stress involving protein oxidation

T₃ administration according to the protocol used resulted in a significant sixfold increment in serum T₃ levels over basal values (controls, 50±10 ng/dl(n=4); T₃-treated rats, 350±20 (n=4); p<0.05), concomitant with a 10% diminution in those of albumin (controls, 3.96±0.05 g/dl (n=3); T₃-treated rats, 3.56±0.14 (n=3); p<0.05), in control rats (Fig. 1A) and T₃-treated animals (Fig. 1B) exhibiting normal liver morphology and comparable (p>0.05) serum AST levels (Fig. 1C). Under these conditions,

Discussion

Cell protection, survival, and functional recovery are elicited by the administration of low doses of T₃ to experimental animals [7]. In the liver, these features are coupled to the activation of the redox-sensitive transcription factors nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), activating protein 1, or nuclear factor-erythroid 2-related factor 2 (Nrf2) upon oxidative stress development, with concurrence of AMPK upregulation for energy supply (Fig. 4

Acknowledgment

This work was supported by Grant 1150104 from the National Fund for Scientific & Technological Development.

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Crosstalk mechanisms in hepatoprotection: Thyroid hormone-docosahexaenoic acid (DHA) and DHA-extra virgin olive oil combined protocols
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Citation Excerpt :
The former mechanism is associated with the genomic action of T3, which is supported by upregulation of the expression of thyroid hormone receptor and retinoic X receptor needed for full activation of gene transcription [63]. Liver FGF21 induction by DHA-T3 could also be due to the ER stress-dependent unfolded protein response (UPR) [67,68], which is triggered by acute T3 administration via activation of the PKR-like ER kinase (PERK) branch of the UPR (Fig. 1A) [48]. Upregulation of liver PPAR-α-FGF21-AMPK signaling by the combined DHA-T3 protocol is functionally operative due to the association with the scaffold proteins β-Klotho, FGFR substrate 2α (FRS2α) and sestrin2, which are induced by T3 [69,70].
Normal liver function includes a number of metabolic processes, secretion of cellular mediators and its role in immunobiology; these require a high energy supply, which is further enhanced under adverse conditions triggering hepatic disorders or injury due to the operation of counteracting mechanisms. Alterations in oxygen availability, such as ischemia-reperfusion (IR) leading to liver inflammation and high-fat diet (HFD)-induced hepatic steatosis, are noxious responses encountered in hepatic surgery and obesity, respectively. Several strategies have been developed to attenuate or prevent these disorders, including thyroid hormone (T₃), docosahexaenoic acid (DHA) and extra virgin olive oil (EVOO). These hormetic agents that exert beneficial effects in the low dose range were shown to abrogate IR-induced liver injury effectively in the case of T₃, DHA, or their combined administration, whereas DHA plus EVOO attenuate HFD-induced hepatic steatosis, although they can induce adverse effects in other experimental settings. The use of combined hepatoprotective protocols (DHA + T₃ or DHA + EVOO) using low doses or reduced supplementation periods is characterized by the stimulation of different types of molecular defensive mechanisms and similar signaling processes that exhibit synergism, thus constituting suitable experimental liver pharmacological preconditioning strategies with possible future clinical applications.
3,3′,5-triiodothyroxine inhibits apoptosis and oxidative stress by the PKM2/PKM1 ratio during oxygen-glucose deprivation/reperfusion AC16 and HCM-a cells T3 inhibits apoptosis and oxidative stress by PKM2/PKM1 ratio
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T3 is inactivated by DIO3, and T3 signaling is impaired by DIO3 in heart diseases [9–11]. Extensive research has suggested that T3 protects cells from OS and apoptosis by improving the redox state of cells [5,12–15]. In the myocardium of infarcted rats, T3 decreases reactive oxygen species (ROS) levels and increases endothelial nitric oxide synthase expression [15].
Oxidative stress (OS) plays a crucial role in the development of myocardial disease, which can induce the dysfunction of cardiac muscle cells. 3,3′,5-triiodothyroxine (T3) is a hormone secreted from the thyroid gland that has been shown to protect cells by improving the redox state and to regulate the expression of pyruvate kinase muscle isozyme (PKM, including two isoforms PKM1 and PKM2). The present study aimed to reveal the key effects of T3 on protecting human myocardial cell lines from oxidative stress and the downstream molecular mechanism. An oxygen-glucose deprivation/reperfusion model (OGDR) and three subtypes of the deiodinase family (DIO1, DIO2, and DIO3), which convert thyroxine (T4) to T3, were tested in this model. Our results show that the expression of DIO1, DIO2 and T3 was downregulated, but DIO3 was upregulated in OGDR-treated AC16 and HCM-a cells. Then, OGDR-treated cells were treated with T3 and T4. The results show that T3 inhibited the expression of reactive oxygen species (ROS) and malonic dialdehyde (MDA), but upregulated glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). The effects of T4 were not notable. T3 also protected OGDR cells from apoptosis and upregulated the PKM2/PKM1 ratio. Further mechanistic studies found that PKM2 inhibition by small interfering RNA (siRNA) could attenuate the anti-OS and anti-apoptotic effects of T3. These findings suggest that T3 can inhibit apoptosis and oxidative stress in OGDR-treated AC16 and HCM-a cells by regulating the PKM2/PKM1 ratio.
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Original ContributionCausal role of oxidative stress in unfolded protein response development in the hyperthyroid state

Highlights

Abstract

Graphical abstract

Section snippets

Animal treatment

T3-induced calorigenesis is associated with liver oxidative stress involving protein oxidation

Discussion

Acknowledgment

J. Hepatol.

Chem.-Biol. Interact

Free Radic. Biol. Med.

J. Surg. Res.

Mol. Cell. Endocrinol.

Toxicol. Lett.

Free Radic. Biol. Med.

Mol. Cell

Methods Enzymol.

Vasc. Pharmacol.

Mol. Cell. Endocrinol.

Brain Res.

Trends Biochem. Sci.

Methods Enzymol.

Semin. Cell Dev. Biol.

J. Hepatol.

Free Radic. Biol. Med.

Int. J. Biochem. Cell Biol.

Semin. Cell Dev. Biol.

Free Radic. Biol. Med.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

Semin. Perinatol.

Preconditioning, organ preservation, and postconditioning to prevent ischemia–reperfusion injury to the liver

Liver Transplant.

Hepatic ischemia–reperfusion injury from bench to bedside

Br. J. Surg.

Thyroid hormone preconditioning: protection against ischemia–reperfusion liver injury in the rat

Hepatology

Recent advances in liver preconditioning: thyroid hormone, n-3 long-chain polyunsaturated fatty acids and iron

World J. Hepatol.

Nrf2-regulated phase-II detoxification enzymes and phase-III transporters are induced by thyroid hormone in rat liver

BioFactors

Thyroid hormone activates rat liver adenosine 5′-monophosphate-activated protein kinase: relation to CaMKKβ, TAK1, and LKB1 expression and energy status

J. Biol. Regul. Agents

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

T₃-induced calorigenesis is associated with liver oxidative stress involving protein oxidation