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  current news   Press   selected story    
     
  6th July 2010  
 

Thioredoxin-interacting Protein (Txnip) Gene Expression: Sensing Oxidative Phosphorylation Status and Glycolytic Rate

 
 




Author
Fa-Xing Yu1, Tin Fan Chai1, Hongpeng He1, Thilo Hagen2,* and Yan Luo1,2, *

1 – Institute of Molecular and Cell Biology, Singapore
2 – Department of Biochemistry, National University of Singapore, Singapore
*Corresponding authors

Published in The Journal of Biological Chemistry, June 17, 2010: epub ahead of print http://www.jbc.org/cgi/doi/10.1074/jbc.M110.108290

Abstract
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 MLX and MondoA (or 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/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 activity implies a mechanism by which the cellular glucose uptake/homeostasis is regulated in response to various metabolic cues, oxidative phosphorylation status and other physiological signals, and this may facilitate our efforts towards understanding metabolism in normal or cancer cells.

 
 

 
 


Figure Legend:
A model linking Txnip expression, glucose transport, glycolysis, OXPHOS and other physiological cues. OXPHOS inhibitors, glutamine and insulin signaling have all been shown to repress Txnip expression; these factors are also known to increase the glycolytic rate. The augmented glycolytic flux may dynamically deplete glycolytic intermediate metabolites normally involved in transmitting glucose signaling to Mondo/MLX activation, which in turn represses Txnip expression. Our data suggest that the metabolites upstream of the GAPDH enzyme, G6P and GADP in particular but others are not ruled out, are candidates that link Txnip expression to glycolytic flux. How Mondo/MLX transcription factors are activated, the nuclear translocation included, and whether the above mentioned relevant metabolites are directly involved in this activation process, are a challenging problem to be addressed in the future. Txnip has an inhibitory role on glucose transport, hence glucose uptake in cells with repressed Txnip expression will be induced – a common theme in many cancerous cells that are addictive to glucose. Glut: glucose transporters

For more information on Yan Luo’s laboratory, please click here.