Fructose 2, 6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes

Catherine Arden, Susan J. Tudhope, John L. Petrie, Ziad H. Al-Oanzi, Kirsty S. Cullen, Alex J. Lange, Howard C. Towle, Loranne Agius

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Glucose metabolism in the liver activates the transcription of various genes encoding enzymes of glycolysis and lipogenesis and also G6pc (glucose-6-phosphatase). Allosteric mechanisms involving glucose 6-phosphate or xylulose 5-phosphate and covalent modification of ChREBP (carbohydrate-response element-binding protein) have been implicated in this mechanism. However, evidence supporting an essential role for a specific metabolite or pathway in hepatocytes remains equivocal. By using diverse substrates and inhibitors and a kinase-deficient bisphosphatase-active variant of the bifunctional enzyme PFK2/FBP2 (6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase), we demonstrate an essential role for fructose 2,6-bisphosphate in the induction of G6pc and other ChREBP target genes by glucose. Selective depletion of fructose 2,6-bisphosphate inhibits glucose-induced recruitment of ChREBP to the G6pc promoter and also induction of G6pc by xylitol and gluconeogenic precursors. The requirement for fructose 2,6-bisphosphate for ChREBP recruitment to the promoter does not exclude the involvement of additional metabolites acting either co-ordinately or at downstream sites. Glucose raises fructose 2,6-bisphosphate levels in hepatocytes by reversing the phosphorylation of PFK2/FBP2 at Ser 32, but also independently of Ser 32 dephosphorylation. This supports a role for the bifunctional enzyme as the phosphometabolite sensor and for its product, fructose 2,6-bisphosphate, as the metabolic signal for substrate-regulated ChREBP-mediated expression of G6pc and other ChREBP target genes.

Original languageEnglish (US)
Pages (from-to)111-123
Number of pages13
JournalBiochemical Journal
Volume443
Issue number1
DOIs
StatePublished - Apr 1 2012

Keywords

  • Carbohydrate-response element-binding protein (ChREBP)
  • Fructose 2,6-bisphosphate
  • Glucose 6-phosphate
  • Glucose-6-phosphatase
  • Hepatocyte

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    Arden, C., Tudhope, S. J., Petrie, J. L., Al-Oanzi, Z. H., Cullen, K. S., Lange, A. J., Towle, H. C., & Agius, L. (2012). Fructose 2, 6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes. Biochemical Journal, 443(1), 111-123. https://doi.org/10.1042/BJ20111280