title: Glucose induces protein targeting to glycogen in hepatocytes by fructose 2,6-bisphosphate-mediated recruitment of MondoA to the promoter.
abstract: In the liver, a high glucose concentration activates transcription of genes encoding glucose 6-phosphatase and enzymes for glycolysis and lipogenesis by elevation in phosphorylated intermediates and recruitment of the transcription factor ChREBP (carbohydrate response element binding protein) and its partner, Mlx, to gene promoters. A proposed function for this mechanism is intracellular phosphate homeostasis. In extrahepatic tissues, MondoA, the paralog of ChREBP, partners with Mlx in transcriptional induction by glucose. We tested for glucose induction of regulatory proteins of the glycogenic pathway in hepatocytes and identified the glycogen-targeting proteins, G(L) and PTG (protein targeting to glycogen), as being encoded by Mlx-dependent glucose-inducible genes. PTG induction by glucose was MondoA dependent but ChREBP independent and was enhanced by forced elevation of fructose 2,6-bisphosphate and by additional xylitol-derived metabolites. It was counteracted by selective depletion of fructose 2,6-bisphosphate with a bisphosphatase-active kinase-deficient variant of phosphofructokinase 2/fructosebisphosphatase 2, which prevented translocation of MondoA to the nucleus and recruitment to the PTG promoter. We identify a novel role for MondoA in the liver and demonstrate that elevated fructose 2,6-bisphosphate is essential for recruitment of MondoA to the PTG promoter. Phosphometabolite activation of MondoA and ChREBP and their recruitment to target genes is consistent with a mechanism for gene regulation to maintain intracellular phosphate homeostasis.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: John L
authors.initials: JL
authors.lastname: Petrie
authors.forename: Ziad H
authors.initials: ZH
authors.lastname: Al-Oanzi
authors.forename: Catherine
authors.initials: C
authors.lastname: Arden
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Tudhope
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
authors.forename: Julius
authors.initials: J
authors.lastname: Kieswich
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Yaqoob
authors.forename: Howard C
authors.initials: HC
authors.lastname: Towle
authors.forename: Loranne
authors.initials: L
authors.lastname: Agius
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D005635:Fructosediphosphates / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D005635:Fructosediphosphates; D047908:Intracellular Signaling Peptides and Proteins; C513412:MLX protein, rat; C442825:Mlxipl protein, rat; C579089:MondoA protein, rat; C491293:Ppp1r5 protein, rat; D015534:Trans-Activators; C027652:fructose 2,6-diphosphate; D006003:Glycogen; D006006:Glycogen Synthase; D005947:Glucose