Nitric Oxide–Dependent Suppression of Thioredoxin-Interacting Protein Expression Enhances Thioredoxin Activity

Schulze, P. Christian; Liu, Heling; Choe, Elizabeth; Yoshioka, Jun; Shalev, Anath; Bloch, Kenneth D.; Lee, Richard T.

doi:10.1161/01.atv.0000248914.21018.f1

Cited by 68 publications

(58 citation statements)

References 33 publications

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“…In addition, it is a potent repressor of TXNIP in beta cells (Fig. 6) and in rat pulmonary artery smooth muscle cells [18]. Taken together, these findings suggest that NO mediates the suppression of TXNIP by activation of insulin signalling.…”

Section: Discussionmentioning

confidence: 64%

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Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

et al. 2009

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Aims/hypothesis In type 2 diabetes, glucose toxicity leads to beta cell apoptosis with decreased beta cell mass as a consequence. Thioredoxin-interacting protein (TXNIP) is a critical mediator of glucose-induced beta cell apoptosis. Since hyperglycaemia leads to elevated serum insulin, we hypothesised that insulin is involved in the regulation of TXNIP protein levels in beta cells. Methods We studied the production of TXNIP in INS-1E beta cells and in islets of Psammomys obesus, an animal model of type 2 diabetes, in response to glucose and different modulators of insulin secretion. Results TXNIP production was markedly augmented in islets from diabetic P. obesus and in beta cells exposed to high glucose concentration. In contrast, adding insulin to the culture medium or stimulating insulin secretion with different secretagogues suppressed TXNIP. Inhibition of glucose and fatty acid-stimulated insulin secretion with diazoxide increased TXNIP production in beta cells. Nitric oxide (NO), a repressor of TXNIP, enhanced insulin signal transduction, whereas inhibition of NO synthase abolished its activation, suggesting that TXNIP inhibition by NO is mediated by stimulation of insulin signalling. Treatment of beta cells chronically exposed to high glucose with insulin reduced beta cell apoptosis. Txnip knockdown mimicking the effect of insulin prevented glucose-induced beta cell apoptosis. Conclusions/interpretation Insulin is a potent repressor of TXNIP, operating a negative feedback loop that restrains the stimulation of TXNIP by chronic hyperglycaemia. Repression of TXNIP by insulin is probably an important compensatory mechanism protecting beta cells from oxidative damage and apoptosis in type 2 diabetes.

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Section: Discussionmentioning

confidence: 64%

“…5). Thus, Nitric oxide is required for the effect of insulin on TXNIP Nitric oxide was shown to suppress TXNIP production in rat pulmonary artery muscle cells [18]. Moreover, NO promoted beta cell survival in response to insulin and IGF-1 [19].…”

Section: Insulin Regulates Txnip In Beta Cellsmentioning

confidence: 98%

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

et al. 2009

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“…Txnip Suppression Involves Transcriptional DeactivationSchulze et al (44) previously demonstrated that exogenous GSNO inhibits the Txnip promoter, and we therefore reasoned that endogenously synthesized NO may operate similarly. As shown in Fig.…”

Section: Txnip Expression Is Negatively Regulated By Endogenousmentioning

confidence: 92%

Thioredoxin-interacting Protein (Txnip) Is a Feedback Regulator of S-Nitrosylation

Forrester

Seth

Hausladen

et al. 2009

Journal of Biological Chemistry

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Nitric oxide exerts a plethora of biological effects via protein S-nitrosylation, a redox-based reaction that converts a protein Cys thiol to a S-nitrosothiol. However, although the regulation of protein S-nitrosylation has been the subject of extensive study, much less is known about the systems governing protein denitrosylation. Most recently, thioredoxin/thioredoxin reductases were shown to mediate both basal and stimulus-coupled protein denitrosylation. We now demonstrate that protein denitrosylation by thioredoxin is regulated dynamically by thioredoxin-interacting protein (Txnip), a thioredoxin inhibitor. Endogenously synthesized nitric oxide represses Txnip, thereby facilitating thioredoxin-mediated denitrosylation. Autoregulation of denitrosylation thus allows cells to survive nitrosative stress. Our findings reveal that denitrosylation of proteins is dynamically regulated, establish a physiological role for thioredoxin in protection from nitrosative stress, and suggest new approaches to manipulate cellular S-nitrosylation.It has become increasingly appreciated that protein S-nitrosylation, the covalent attachment of a nitroso group to a cysteine thiol side chain, is a principle mechanism by which nitric oxide modulates numerous cellular functions and phenotypes (1, 2). These include G-protein-coupled receptor signaling (3-5), death receptor-mediated apoptosis (6 -9), vesicular trafficking (10 -12), stimulation of prostaglandin synthesis (13-15), hypoxia-dependent control of blood flow (16 -18), and the unfolded protein response (19). In addition, aberrant S-nitrosylation is implicated in pathologies such as tumor initiation and growth (20, 21), neurodegeneration (19,22,23), and pulmonary hypertension (24).The three isoforms of nitric-oxide synthase (neuronal NOS/ NOS1, iNOS/NOS2, 2 and endothelial NOS/NOS3) are well established mediators of S-nitrosylation, and numerous studies have demonstrated that their localization is critical for S-nitrosylation of target proteins. For example, binding of iNOS to COX2 is required for S-nitrosylation and activation of prostaglandin synthesis (13), whereas the subcellular localization of endothelial NOS is a major determinant of S-nitrosylation-mediated protein trafficking (25). Moreover, although it is generally assumed that S-nitrosylation reactions are nonenzymatic, there is precedence for hemoglobin-dependent S-nitrosylation of the anion exchanger protein AE1 (26) and ceruloplasmin-dependent S-nitrosylation of glypican-1 (27) and GSH (28), consistent with a recent report that metalloproteins may play a general role in SNO synthesis (29).By contrast with progress in elucidating the enzymatic determinants of S-nitrosylation, the intracellular mediators of denitrosylation and their possible contributions to overall Snitrosylation status have only recently gained attention. By analogy to phosphorylation (where kinases and phosphatases together regulate phosphorylation), the steady-state level of S-nitrosylation is the net difference between nitrosylation and denitros...

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“…Thus, the Txnip expression is tightly correlated with the OXPHOS status, and a functional proton pumping electron transport chain, as well as ATP synthesis, is essential for maintaining normal Txnip mRNA levels. NO was earlier shown to be able to repress Txnip expression; however, this was without a revelation that it might be linked to a role in inhibiting OXPHOS (26). The effect of NaN 3 and DETA/NO on Txnip mRNA expression was tested in other cell lines, U2OS, WI-39, Namalwa B, and Jurkat T cells included, and the Txnip expression was repressed dramatically in all tested cell lines (data not shown), suggesting that the action of OXPHOS inhibitors on the Txnip expression is most likely a general phenomenon.…”

Section: Inhibition Of Oxphos Down-regulates Txnip Mrna Levels-mentioning

confidence: 99%

Thioredoxin-interacting Protein (Txnip) Gene Expression

Chai

et al. 2010

Journal of Biological Chemistry

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Thioredoxin-interacting protein (Txnip) has important functions in regulating cellular metabolism including glucose utilization; the expression of the Txnip gene is sensitive to the availability of glucose and other fuels. Here, we show that Txnip expression is down-regulated at the transcriptional level by diverse inhibitors of mitochondrial oxidative phosphorylation (OXPHOS). The effect of these OXPHOS inhibitors is mediated by earlier identified carbohydrate-response elements (ChoREs) on the Txnip promoter and the ChoRE-associated transcription factors Max-like protein X (MLX) and MondoA (or carbohydrate-response element-binding protein (ChREBP)) involved in glucose-induced Txnip expression, suggesting that inhibited oxidative phosphorylation compromises glucose-induced effects on Txnip expression. We also show that the OXPHOS inhibitors repress the Txnip transcription most likely by inducing the glycolytic rate, and increased glycolytic flux decreases the levels of glycolytic intermediates important for the function of MLX and MondoA (or ChREBP). Our findings suggest that the Txnip expression is tightly correlated with glycolytic flux, which is regulated by oxidative phosphorylation status. The identified link between the Txnip expression and glycolytic activityimpliesamechanismbywhichthecellularglucoseuptake/ homeostasis is regulated in response to various metabolic cues, oxidative phosphorylation status, and other physiological signals, and this may facilitate our efforts toward understanding metabolism in normal or cancer cells. Thioredoxin-interacting-protein (Txnip)3 plays important roles in diverse physiological or pathological processes (reviewed in Ref 1). In many cancer cell lines or cancer tissues, the expression of the Txnip gene is down-regulated; because Txnip can inhibit cell proliferation and promote apoptosis, it is thought that low Txnip expression may contribute to cancer development (2-8). Recently, Txnip was identified as a negative regulator for cellular glucose uptake (9 -11); Txnip knockout mice exhibit abnormalities in glucose and lipid metabolism (4,(12)(13)(14). These observations are in line with critical function(s) of Txnip in metabolic control.The expression of the Txnip gene is sensitive to many nutritional factors. Txnip was originally identified as a vitamin D up-regulated protein (VDUP1 (15)), and the Txnip expression was later shown to be induced by glucose, which is mediated by carbohydrate-response elements (ChoREs (16 -18)) and associated transcription factors Max-like protein X (MLX) and Mondo (MondoA or ChoRE-binding protein (ChREBP, which is also dubbed as MondoB) (18 -20)). Moreover, the Txnip expression is modulated by glutamine, potentially through glutaminolysis, fatty acids, and an array of adenosine-containing molecules (21-23). The capability of the Txnip gene to sense diverse nutrients and to regulate their utilization implies a mechanism for cells to integrate different signaling pathways evoked by diverse nutritional factors.In the current study, we wished t...

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Nitric Oxide–Dependent Suppression of Thioredoxin-Interacting Protein Expression Enhances Thioredoxin Activity

Abstract: Objective-Cellular redox balance is regulated by enzymatic and nonenzymatic systems and freely diffusible nitric oxide (NO) promotes antioxidative mechanisms. We show the NO-dependent transcriptional regulation of the antioxidative thioredoxin system.

Cited by 68 publications

References 33 publications

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

Thioredoxin-interacting Protein (Txnip) Is a Feedback Regulator of S-Nitrosylation

Thioredoxin-interacting Protein (Txnip) Gene Expression

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