title: Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver.
abstract: OBJECTIVE
  In liver, the glucose-responsive transcription factor ChREBP plays a critical role in converting excess carbohydrates into triglycerides through de novo lipogenesis. Although the importance of ChREBP in glucose sensing and hepatic energy utilization is strongly supported, the mechanism driving its activation in response to glucose in the liver is not fully understood. Indeed, the current model of ChREBP activation, which depends on Serine 196 and Threonine 666 dephosphorylation, phosphatase 2A (PP2A) activity, and xylulose 5-phosphate (X5P) as a signaling metabolite, has been challenged.
  
  
  METHODS
  We inhibited PP2A activity in HepG2 cells through the overexpression of SV40 small t antigen and addressed the importance of ChREBP dephosphorylation on Ser-196 using a phospho-specific antibody. To identify the exact nature of the metabolite signal required for ChREBP activity in liver, we focused on the importance of G6P synthesis in liver cells, through the modulation of glucose 6-phosphate dehydrogenase (G6PDH) activity, the rate-limiting enzyme of the pentose phosphate pathway in hepatocytes, and in HepG2 cells using both adenoviral and siRNA approaches.
  
  
  RESULTS
  In contrast to the current proposed model, our study reports that PP2A activity is dispensable for ChREBP activation in response to glucose and that dephosphorylation on Ser-196 is not sufficient to promote ChREBP nuclear translocation in the absence of a rise in glucose metabolism. By deciphering the respective roles of G6P and X5P as signaling metabolites, our study reveals that G6P produced by GK, but not X5P, is essential for both ChREBP nuclear translocation and transcriptional activity in response to glucose in liver cells.
  
  
  CONCLUSIONS
  Altogether, our study, by reporting that G6P is the glucose-signaling metabolite, challenges the PP2A/X5P-dependent model currently described for ChREBP activation in response to glucose in liver.
authors.affiliation: Inserm, U1016, Paris, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Dentin
authors.forename: Lidia
authors.initials: L
authors.lastname: Tomas-Cobos
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Jane
authors.initials: J
authors.lastname: Leopold
authors.forename: Jean
authors.initials: J
authors.lastname: Girard
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
mesh_terms: D021581:Active Transport, Cell Nucleus; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008954:Models, Biological; D010427:Pentose Phosphate Pathway; D010428:Pentosephosphates / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C116385:MLXIPL protein, human; D010428:Pentosephosphates; D034741:RNA, Small Interfering; D019298:Glucose-6-Phosphate; C031625:xylulose-5-phosphate; D005954:Glucosephosphate Dehydrogenase; D054648:Protein Phosphatase 2; D005947:Glucose