ChREBP binding to fatty acid synthase and L-type pyruvate kinase genes is stimulated by glucose in pancreatic β-cells

Gabriela da Silva Xavier, Guy A Rutter, Frédérique Diraison, Chrysovalantis Andreolas, Isabelle Leclerc

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)
154 Downloads (Pure)

Abstract

Pancreatic β-cell dysfunction is central to the pathogenesis of type 2 diabetes and may involve secretory failure through glucolipotoxity. The relative importance of the transcription factors carbohydrate-responsive element binding protein (ChREBP), sterol-responsive element binding protein-1c (SREBP-1c), and upstream stimulatory factor (USF) in the induction of lipogenic genes by glucose remains unclear. By confocal imaging, we show that ChREBP translocates to the nucleus in MIN6 β cells in response to glucose. Both ChREBP and SREBP-1c were required for the induction of the fatty acid synthase (FAS) promoter by glucose, and chromatin immunoprecipitation (ChIP) assay revealed that glucose induced the binding of both ChREBP and SREBP-1c to the FAS promoter without affecting USF2 binding. By contrast, ChIP assay revealed that high glucose prompted direct binding of ChREBP, but not SREBP-1c or USF2, to the liver-type pyruvate kinase (L-PK) promoter. This event was indispensable for the induction of the L-PK gene by glucose, as demonstrated by RNA silencing, single-cell promoter analysis, and quantitative real-time PCR. We conclude that ChREBP is a critical regulator of lipogenic genes in the β cell and may play a role in the development of glucolipotoxicity and β cell failure through alteration of gene expression in type 2 diabetes.

Original languageEnglish
Pages (from-to)2482-2491
Number of pages10
JournalJournal of Lipid Research
Volume47
Issue number11
DOIs
Publication statusPublished - Nov 2006

Keywords

  • Active Transport, Cell Nucleus
  • Animals
  • Apoptosis
  • Base Sequence
  • Fatty Acid Synthases/metabolism
  • Gene Silencing
  • Glucose/metabolism
  • Insulin-Secreting Cells/metabolism
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins/metabolism
  • Protein Binding
  • Pyruvate Kinase/metabolism
  • RNA, Small Interfering/metabolism
  • Transcription Factors/metabolism
  • Triglycerides/metabolism

Fingerprint

Dive into the research topics of 'ChREBP binding to fatty acid synthase and L-type pyruvate kinase genes is stimulated by glucose in pancreatic β-cells'. Together they form a unique fingerprint.

Cite this