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首页> 外文学位 >Regulation of thioredoxin-interacting protein in response to changes in metabolic and energetic state.
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Regulation of thioredoxin-interacting protein in response to changes in metabolic and energetic state.

机译：调节硫氧还蛋白相互作用蛋白，以响应代谢和能量状态的变化。

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摘要

Thioredoxin-interacting protein (TXNIP) plays an important role in regulating glucose metabolism. The expression of TXNIP is directly regulated by the MondoA:Mlx transcription factor complexes in response to changes in metabolic and energetic state. MondoA:Mlx complexes activate TXNIP expression by sensing glucose-6-phosphate (G6P), the first intermediate of glycolysis. Here, we investigate how bioenergetic changes regulate MondoA:Mlx activity and TXNIP expression. We show that TXNIP expression is also stimulated by 5-aminoimidazole-4-carboxamide ribofuranoside (AICAR) and adenosine. This effect of AICAR and adenosine is mediated by MondoA:Mlx transcriptional activity, but is independent of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Consistent with the role of MondoA in glucose-dependent transcription, AICAR and adenosine effect on TXNIP expression depends on glucose availability. To activate TXNIP expression, AICAR and adenosine must enter into cells and be converted to adenine nucleotides. These findings suggest that MondoA:Mlx complexes sense the levels of adenine nucleotides as well as G6P. We also show that oxidative phosphorylation (OXPHOS) inhibitors suppress adenosine-induction of TXNIP. This repressive effect of OXPHOS inhibitors is most likely mediated by increased glycolytic rate and decreased mitochondrial adenosine triphosphate (ATP) levels, which might deplete G6P levels. The suppression of TXNIP by OXPHOS inhibitors was partially restored by combination of 2-deoxyglucose (2DG) and adenosine but not by 2DG alone, suggesting the involvement of mitochondrial ATP on TXNIP expression. In addition to transcriptional regulation, we show that TXNIP protein levels were reduced by AMPK activation with AICAR. High dose of AICAR treatment accelerates TXNIP protein degradation in an AMPK-dependent manner. With the fact that TXNIP negatively regulate glucose uptake, our findings imply that cells control TXNIP-dependent feedback loop of glucose flux by regulating TXNIP levels through MondoA and AMPK in response to metabolic and energetic changes. Thus, we propose that TXNIP is a critical mediator of integrating information about metabolic and energetic status to maintain energy homeostasis.
机译：硫氧还蛋白相互作用蛋白（TXNIP）在调节葡萄糖代谢中起重要作用。 TXNIP的表达直接受MondoA：Mlx转录因子复合物调节，以响应代谢和能量状态的变化。 MondoA：Mlx复合物通过感测糖酵解的第一个中间体6-磷酸葡萄糖（G6P）来激活TXNIP表达。在这里，我们调查生物能变化如何调节MondoA：Mlx活性和TXNIP表达。我们显示TXNIP表达也受到5-氨基咪唑-4-羧酰胺核呋喃糖苷（AICAR）和腺苷的刺激。 AICAR和腺苷的这种作用由MondoA：Mlx转录活性介导，但独立于单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）。与MondoA在葡萄糖依赖性转录中的作用相一致，AICAR和腺苷对TXNIP表达的作用取决于葡萄糖的利用率。为了激活TXNIP表达，AICAR和腺苷必须进入细胞并转化为腺嘌呤核苷酸。这些发现表明，MondoA：Mlx复合物可检测腺嘌呤核苷酸以及G6P的水平。我们还显示，氧化磷酸化（OXPHOS）抑制剂抑制TXNIP的腺苷诱导。 OXPHOS抑制剂的这种抑制作用很可能是由糖酵解速率增加和线粒体三磷酸腺苷（ATP）水平降低所介导的，这可能会耗尽G6P水平。 OXPHOS抑制剂对TXNIP的抑制作用可通过2-脱氧葡萄糖（2DG）和腺苷的组合部分恢复，但不能单独通过2DG来恢复，这表明线粒体ATP参与TXNIP表达。除转录调控外，我们还表明，通过AICAR的AMPK激活，TXNIP蛋白水平降低了。高剂量的AICAR治疗以AMPK依赖性方式加速TXNIP蛋白降解。有了TXNIP负调节葡萄糖摄取这一事实，我们的发现暗示细胞通过响应于代谢和能量变化而通过MondoA和AMPK调节TXNIP水平来控制葡萄糖流量的TXNIP依赖性反馈回路。因此，我们认为TXNIP是整合有关代谢和能量状态信息以维持能量稳态的关键介质。

著录项

  • 作者

    Han, Kyoung Sim.;

  • 作者单位

    The University of Utah.;

  • 授予单位 The University of Utah.;
  • 学科 Biology Molecular.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 117 p.
  • 总页数 117
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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