Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation

Diabetes. 2015 Dec;64(12):4158-70. doi: 10.2337/db15-0239. Epub 2015 Sep 17.


Carbohydrate-responsive element-binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic β-cells in rodents and humans. The full-length isoform (ChREBPα) has a low glucose inhibitory domain (LID) that restrains the transactivation domain when glucose catabolism is minimal. A novel isoform of ChREBP (ChREBPβ) was recently described that lacks the LID domain and is therefore constitutively and more potently active. ChREBPβ has not been described in β-cells nor has its role in glucose-stimulated proliferation been determined. We found that ChREBPβ is highly expressed in response to glucose, particularly with prolonged culture in hyperglycemic conditions. In addition, small interfering RNAs that knocked down ChREBPβ transcripts without affecting ChREBPα expression or activity decreased glucose-stimulated expression of carbohydrate response element-containing genes and glucose-stimulated proliferation in INS-1 cells and in isolated rat islets. Quantitative chromatin immunoprecipitation, electrophoretic mobility shift assays, and luciferase reporter assays were used to demonstrate that ChREBP binds to a newly identified powerful carbohydrate response element in β-cells and hepatocytes, distinct from that in differentiated 3T3-L1 adipocytes. We conclude that ChREBPβ contributes to glucose-stimulated gene expression and proliferation in β-cells, with recruitment of ChREBPα to tissue-specific elements of the ChREBPβ isoform promoter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes, White / cytology
  • Adipocytes, White / metabolism
  • Adipocytes, White / pathology
  • Adult
  • Alternative Splicing
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cadaver
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Electrophoretic Mobility Shift Assay
  • HeLa Cells
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / metabolism*
  • Hyperglycemia / pathology
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Mice
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Interference
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • MLXIPL protein, human
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • Protein Isoforms
  • Recombinant Proteins
  • Transcription Factors
  • Wbscr14 protein, rat