Glucose-6-phosphate mediates activation of the carbohydrate responsive binding protein (ChREBP)

Ming V. Li, Weiqin Chen, Romain N. Harmancey, Alli M. Nuotio-Antar, Minako Imamura, Pradip Saha, Heinrich Taegtmeyer, Lawrence Chan

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Carbohydrate response element binding protein (ChREBP) is a Mondo family transcription factor that activates a number of glycolytic and lipogenic genes in response to glucose stimulation. We have previously reported that high glucose can activate the transcriptional activity of ChREBP independent of the protein phosphatase 2A (PP2A)-mediated increase in nuclear entry and DNA binding. Here, we found that formation of glucose-6-phosphate (G-6-P) is essential for glucose activation of ChREBP. The glucose response of GAL4-ChREBP is attenuated by d-mannoheptulose, a potent hexokinase inhibitor, as well as over-expression of glucose-6-phosphatase (G6Pase); kinetics of activation of GAL4-ChREBP can be modified by exogenously expressed GCK. Further metabolism of G-6-P through the two major glucose metabolic pathways, glycolysis and pentose-phosphate pathway, is not required for activation of ChREBP; over-expression of glucose-6-phosphate dehydrogenase (G6PD) diminishes, whereas RNAi knockdown of the enzyme enhances, the glucose response of GAL4-ChREBP, respectively. Moreover, the glucose analogue 2-deoxyglucose (2-DG), which is phosphorylated by hexokinase, but not further metabolized, effectively upregulates the transcription activity of ChREBP. In addition, over-expression of phosphofructokinase (PFK) 1 and 2, synergistically diminishes the glucose response of GAL4-ChREBP. These multiple lines of evidence support the conclusion that G-6-P mediates the activation of ChREBP.

Original languageEnglish (US)
Pages (from-to)395-400
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume395
Issue number3
DOIs
StatePublished - May 7 2010
Externally publishedYes

Keywords

  • Carbohydrate response element binding protein (ChREBP)
  • Glucose-6-phosphate (G-6-P)
  • Transcriptional activation

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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