ChREBP binding to fatty acid synthase and L-type pyruvate kinase genes is stimulated by glucose in pancreatic beta-cells.
Pancreatic beta-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 beta 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 beta cell and may play a role in the development of glucolipotoxicity and beta cell failure through alteration of gene expression in type 2 diabetes.
da Silva Xavier
Gabriela
G
Henry Wellcome Laboratories for Integrated Cell Signalling, Department of Biochemistry, University of Bristol, Bristol, UK.
Rutter
Guy A
GA
Diraison
Frédérique
F
Andreolas
Chrysovalantis
C
Leclerc
Isabelle
I
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D064429:Fatty Acid Synthases / Q000378:metabolism*; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D011770:Pyruvate Kinase / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014280:Triglycerides; D064429:Fatty Acid Synthases; D011770:Pyruvate Kinase; D005947:Glucose