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 language | English |
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Pages (from-to) | 2482-2491 |
Number of pages | 10 |
Journal | Journal of Lipid Research |
Volume | 47 |
Issue number | 11 |
DOIs | |
Publication status | Published - 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