Carbohydrate-responsive element-binding protein (ChREBP) is a negative regulator of ARNT/HIF-1beta gene expression in pancreatic islet beta-cells

Nafeesa A Noordeen, Tarnjit K Khera, Gao Sun, E Rebecca Longbottom, Timothy J Pullen, Gabriela da Silva Xavier, Guy A Rutter, Isabelle Leclerc

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)


OBJECTIVE: Carbohydrate-responsive element-binding protein (ChREBP) is a transcription factor that has been shown to regulate carbohydrate metabolism in the liver and pancreatic beta-cells in response to elevated glucose concentrations. Because few genes have been identified so far as bona fide ChREBP-target genes, we have performed a genome-wide analysis of the ChREBP transcriptome in pancreatic beta-cells.

RESEARCH DESIGN AND METHODS: Chromatin immunoprecipitation and high-density oligonucleotide tiling arrays (ChIP-chip; Agilent Technologies) using MIN6 pancreatic beta-cell extracts were performed together with transcriptional and other analysis using standard techniques.

RESULTS: One of the genes identified by ChIP-chip and linked to glucose sensing and insulin secretion was aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor-1beta (HIF-1beta), a transcription factor implicated in altered gene expression and pancreatic-islet dysfunction in type 2 diabetes. We first confirmed that elevated glucose concentrations decreased ARNT/HIF-1beta levels in INS-1 (832/13) cells and primary mouse islets. Demonstrating a role for ChREBP in ARNT gene regulation, ChREBP silencing increased ARNT mRNA levels in INS-1 (832/13) cells, and ChREBP overexpression decreased ARNT mRNA in INS-1 (832/13) cells and primary mouse islets. We demonstrated that ChREBP and Max-like protein X (MLX) bind on the ARNT/HIF-1beta promoter on the proximal region that also confers the negative glucose responsiveness.

CONCLUSIONS: These results demonstrate that ChREBP acts as a novel repressor of the ARNT/HIF-1beta gene and might contribute to beta-cell dysfunction induced by glucotoxicity.

Original languageEnglish
Pages (from-to)153-60
Number of pages8
Issue number1
Publication statusPublished - Jan 2010


  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator/antagonists & inhibitors
  • Cell Culture Techniques
  • Chromatin/isolation & purification
  • DNA Primers
  • Gene Expression Regulation/physiology
  • Glucose/toxicity
  • Insulin-Secreting Cells/cytology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Nuclear Proteins/metabolism
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic
  • RNA/genetics
  • Rats
  • Transcription Factors/metabolism
  • Transfection


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