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Papers In Press, published online ahead of print August 4, 2006
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Department of Biochemistry, University of Bristol, School of Medical Sciences, Bristol, Avon BS8 1TD
Corresponding Author: i.leclerc{at}bristol.ac.uk
Pancreatic
Revised on August 2, 2006
Accepted on August 4, 2006
Carbohydrate responsive-element binding protein (chREBP) binding to fatty acid synthase and L-type pyruvate kinase genes is stimulated by glucose in pancreatic MIN6
-cells
-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 Response 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 -cells in response to glucose. Both ChREBP and SREBP-1c were required for the induction of 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 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 -cell and may play a role in the development of glucolipotoxicity and -cell failure through alteration of gene expression in type 2 diabetes.
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