Sterol regulatory element-binding proteins are transcriptional regulators of the thyroglobulin gene in thyroid cells

Wen, Gaiping; Eder, Klaus; Ringseis, Robert

doi:10.1016/j.bbagrm.2016.06.004

Cited by 8 publications

(9 citation statements)

References 64 publications

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Section: Resultsmentioning

confidence: 99%

“…Despite the well known role of TTF-1, TTF-2 and PAX-8 in regulating genes involved in thyroid hormone synthesis, we have recently identified SREBP-1c and SREBP-2 as novel transcriptional regulators of NIS, TPO and TG [ 27 – 29 ]. Using reporter gene, DNA binding and chromatin immunoprecipitation assays, we could identify specific SREBP binding sites, called sterol response elements (SRE), within different regulatory regions of NIS, TPO and TG [ 27 – 29 ]. While SREBPs were initially discovered as master transcription factors of cholesterol, fatty acid, triacylglycerol and phospholipid synthesis [ 26 ], the data from our group indicated that SREBPs have functions beyond lipid synthesis, such as hormone synthesis, at least in the thyroid.…”

Section: Resultsmentioning

confidence: 99%

“…FRTL-5 cells were obtained from Cell lines service (Eppelheim, Germany). Cells were cultured in Ham´s F12 medium supplemented with 5% newborn calf serum, 1% antibiotic-antimycotic-mixture and a six-hormone mixture as described recently [ 29 ]. Medium was changed every two days.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently reported that sterol regulatory element-binding proteins (SREBP)-1c and SREBP-2, which have been initially identified as master regulators of genes involved in lipid synthesis and uptake such as fatty acid synthase (FASN), glycerol-3-phosphate acyltransferase, mitochondrial (GPAM), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and LDL receptor (LDLR) [ 26 ], also act as transcriptional regulators of NIS, TPO and TG and are under the control of TSH in thyrocytes [ 27 – 29 ]. Despite the role of SREBPs as transcriptional regulators of NIS, TPO and TG, we hypothesized that SREBPs are activated in thyrocytes during ER stress.…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes

2017

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Endoplasmic reticulum (ER) stress is characterized by the accumulation of misfolded proteins due to an impairment of ER quality control pathways leading to the activation of a defense system, called unfolded protein response (UPR). While thyrocytes are supposed to be highly susceptible to environmental conditions that cause ER stress due to the synthesis of large amounts of secretory proteins required for thyroid hormone synthesis, systematic investigations on the effect of ER stress on expression of key genes of thyroid hormone synthesis and their transcriptional regulators are lacking. Since the aim of the ER stress-induced UPR is to restore ER homeostasis and to facilitate cell survival through transient shutdown of ribosomal protein translation, we hypothesized that the expression of genes involved in thyroid hormone synthesis and their transcriptional regulators, all of which are not essential for cell survival, are down-regulated in thyrocytes during ER stress, while sterol regulatory element-binding proteins (SREBPs) are activated during ER stress in thyrocytes. Treatment of FRTL-5 thyrocytes with the ER stress inducer tunicamycin (TM) dose-dependently increased the mRNA and/or protein levels of known UPR target genes, stimulated phosphorylation of the ER stress sensor protein kinase RNA-like ER kinase (PERK) and of the PERK target protein eukaryotic initiation factor 2α (eIF2α) and caused splicing of the ER stress-sensitive transcription factor X-box binding protein (XBP-1) (P < 0.05). The mRNA levels and/or protein levels of genes involved in thyroid hormone synthesis, sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), their transcriptional regulators and thyrotropin (TSH) receptor and the uptake of Na125I were reduced at the highest concentration of TM tested (0.1 μg/mL; P < 0.05). Proteolytic activation of the SREBP-1c pathway was not observed in FRTL-5 cells treated with TM, whereas TM reduced proteolytic activation of the SREBP-2 pathway at 0.1 μg TM/mL (P < 0.05). In conclusion, the expression of key genes involved in thyroid hormone synthesis and their critical regulators and of the TSH receptor as well as the uptake of iodide is attenuated in thyrocytes during mild ER stress. Down-regulation of NIS, TPO and TG during ER stress is likely the consequence of impaired TSH/TSHR signaling in concert with reduced expression of critical transcriptional regulators of these genes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes

2017

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“…These proteins now called SERBPs have been found to be involved in more functions than just lipid and cholesterol metabolism [202], [203], [204], [205] as they can regulate the ATP citrate-lyase gene [206]. More interesting is the fact that they can regulate some of the elements involved in thyroid function such as the NIS gene in the thyroid [207] as well as mammary epithelial cells [208], the thyroid peroxidase [209], and the thyroglobulin gene [210]. Besides these relations to thyroid function there are also interaction between the SERBPs and steroidogenesis.…”

Section: A New Player: Sterol Regulatory Element Binding Proteins - Smentioning

confidence: 99%

Applying a systems approach to thyroid physiology: Looking at the whole with a mitochondrial perspective instead of judging single TSH values or why we should know more about mitochondria to understand metabolism

Moncayo¹,

Moncayo²

2017

BBA Clinical

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Classical thinking in endocrine physiology squeezes our diagnostic handling into a simple negative feedback mechanism with a controller and a controlled variable. In the case of the thyroid this is reduced to TSH and fT3 and fT4, respectively. The setting of this tight notion has no free space for any additions. In this paper we want to challenge this model of limited application by proposing a construct based on a systems approach departing from two basic considerations. In first place since the majority of cases of thyroid disease develop and appear during life it has to be considered as an acquired condition. In the second place, our experience with the reversibility of morphological changes makes the autoimmune theory inconsistent.While medical complexity can expand into the era of OMICS as well as into one where manipulations with the use of knock-outs and -ins are common in science, we have preferred to maintain a simple and practical approach. We will describe the interactions of iron, magnesium, zinc, selenium and coenzyme Q10 with the thyroid axis. The discourse will be then brought into the context of ovarian function, i.e. steroid hormone production. Finally the same elemental players will be presented in relation to the basic mitochondrial machinery that supports the endocrine.We propose that an intact mitochondrial function can guard the normal endocrine function of both the thyroid as well as of the ovarian axis. The basic elements required for this function appear to be magnesium and iron. In the case of the thyroid, magnesium-ATP acts in iodine uptake and the heme protein peroxidase in thyroid hormone synthesis. A similar biochemical process is found in steroid synthesis with cholesterol uptake being the initial energy-dependent step and later the heme protein ferredoxin 1 which is required for steroid synthesis. Magnesium plays a central role in determining the clinical picture associated with thyroid disease and is also involved in maintaining fertility. With the aid of 3D sonography patients needing selenium and/or coenzyme Q10 can be easily identified. By this we firmly believe that physicians should know more about basic biochemistry and the way it fits into mitochondrial function in order to understand metabolism. Contemplating only TSH is highly reductionistic.OutlineAuthor's profiles and motivation for this analysisThe philosophical alternatives in science and medicineReductionism vs. systems approach in clinical thyroid disease guidelinesThe entry into complexity: the involvement of the musculoskeletal systemIntegrating East and West: teachings from Chinese Medicine and from evidence based medicine (EBM)Can a mathematical model represent complexity in the daily thyroid practice?How effective is thyroxine treatment?Resolving the situation of residual symptoms in treated patients with thyroid diseaseImportance of iron, zinc and magnesium in relation to thyroid functionPutting together new concepts related to thyroid function for a systems approachExpanding our model into general aspects of ...

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Astaxanthin attenuates hepatic steatosis in high-fat diet-fed rats by suppressing microRNA-21 via transactivation of nuclear factor erythroid 2-related factor 2

Shatoor

Almohiy

2021

J Physiol Biochem

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Sterol regulatory element-binding proteins are transcriptional regulators of the thyroglobulin gene in thyroid cells

Cited by 8 publications

References 64 publications

Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes

Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes

Applying a systems approach to thyroid physiology: Looking at the whole with a mitochondrial perspective instead of judging single TSH values or why we should know more about mitochondria to understand metabolism

Astaxanthin attenuates hepatic steatosis in high-fat diet-fed rats by suppressing microRNA-21 via transactivation of nuclear factor erythroid 2-related factor 2

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