Activation and repression of glucose-stimulated ChREBP requires the concerted action of multiple domains within the MondoA conserved region

Davies, Michael N.; O’Callaghan, Brennon; Towle, Howard C.

doi:10.1152/ajpendo.00349.2010

Cited by 23 publications

(38 citation statements)

References 26 publications

(55 reference statements)

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“…However, the region that is critical for glucose regulation has been mapped to the N-terminal 300 amino acids of both factors, termed the Mondo conserved region. This region is highly conserved between ChREBP and MondoA and likely serves to bind to the active glucose metabolite or glucose-sensing factor (50)(51)(52)(53). Previous studies on the activation of ChREBP and MondoA have been performed in different cell models (42).…”

Section: Discussionmentioning

confidence: 99%

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Petrie

Al‐Oanzi

Arden

et al. 2013

Molecular and Cellular Biology

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dIn 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.

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Section: Discussionmentioning

confidence: 99%

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Petrie

Al‐Oanzi

Arden

et al. 2013

Molecular and Cellular Biology

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“…NES, nuclear export signal; NLS, nuclear localization signal; bHLHZ, basic helix-loop-helix leucine zipper bound by nuclear export factor, Crm1 (Fig. 2) [34][35][36][37][38]. MCR III is constitutively bound by 14-3-3, which is needed for glucose responsiveness [36].…”

Section: O-linked Glcnacylationmentioning

confidence: 99%

“…ChREBP-α contains a glucose-sensing module (GSM) (Fig. 2) [34][35][36][37][38]. GSM contains a low-glucose inhibitory domain (LID, residues ) and a glucose-response activation conserved element (GRACE, residues 197-298) (Fig.…”

Section: Intramolecular Glucose Sensing Module [Glucoseresponse Activmentioning

confidence: 99%

“…GSM contains a low-glucose inhibitory domain (LID, residues ) and a glucose-response activation conserved element (GRACE, residues 197-298) (Fig. 2) [34][35][36][37][38]. Mondo conserved region (MCR) is composed of five distinct subdomains, MCR I-V, of which MCR I-IV corresponds to LID (Fig.…”

Section: Intramolecular Glucose Sensing Module [Glucoseresponse Activmentioning

confidence: 99%

“…Mondo conserved region (MCR) is composed of five distinct subdomains, MCR I-V, of which MCR I-IV corresponds to LID (Fig. 2) [34][35][36][37][38]. ChREBP-α contains a nuclear localization signal (NLS) in MCR IV and two nuclear export signals (NES1 and NES2) …”

Section: Intramolecular Glucose Sensing Module [Glucoseresponse Activmentioning

confidence: 99%

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Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

Iizuka

2013

Endocr J

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Abstract. Carbohydrate response element binding protein (ChREBP) is a transcription factor activated by glucose that is highly expressed in liver, pancreatic β-cells, brown and white adipose tissues, and muscle. We reported that hepatic suppression of the Chrebp gene improves hepatic steatosis, glucose intolerance, and obesity in genetically obese mice. Moreover, we have studied the role of ChREBP with special reference to feedforward and feedback looping in liver and pancreatic β-cells. Recently, several groups reported that (1) glucose activates ChREBP-α transactivity and in turn ChREBP-α induces ChREBP-β on both transcriptional and translational levels in adipose tissues, and (2) ChREBP regulates glucose transporter type 4 mRNA levels, which may affect glucose uptake in adipose tissues. Moreover, in adipose tissues of obese patients, Chrebpb mRNA levels were much lower than those in lean subjects, while the levels were much higher in liver of obese patients than those in lean subjects. These findings suggest that Chrebpb mRNA levels are different in various tissues and probably in the stages of diabetes mellitus. Herein, we review recent progress in the study of ChREBP with special references to (1) the mechanisms regulating ChREBP transactivity (posttranslational modifications, intramolecular glucose sensing module, feedforward mechanism, and the feedback loop between ChREBP and its target genes), and (2) the role of ChREBP in liver, pancreatic islets and adipose tissues. Understanding the role of ChREBP in each tissue will provide important insight into the pathogenesis of metabolic syndrome.

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Transcriptional Regulation of De Novo Lipogenesis in Liver

Zhang

Yin

2015

Hepatic De Novo Lipogenesis and Regulation of Metabolism

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Activation and repression of glucose-stimulated ChREBP requires the concerted action of multiple domains within the MondoA conserved region

Cited by 23 publications

References 26 publications

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

Recent progress on the role of ChREBP in glucose and lipid metabolism [Review]

Transcriptional Regulation of De Novo Lipogenesis in Liver

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