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Journal of Lipid Research, Vol. 47, 2482-2491, November 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Gabriela da Silva Xavier^1,, Guy A. Rutter^1,, Frédérique Diraison^*, Chrysovalantis Andreolas^* and Isabelle Leclerc^2,

^* From the Henry Wellcome Laboratories for Integrated Cell Signalling, Department of Biochemistry, University of Bristol, Bristol, BS8 1TD
Section of Cell Biology, Division of Medicine, Imperial College, Exhibition Road, London SW7 2AZ, UK

Published, JLR Papers in Press, August 4, 2006.

¹ G. da Silva Xavier and G. A. Rutter contributed equally to this work.

² To whom correspondence should be addressed. e-mail: i.leclerc{at}imperial.ac.uk

Pancreatic ß-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 ß 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 ß cell and may play a role in the development of glucolipotoxicity and ß cell failure through alteration of gene expression in type 2 diabetes.

Supplementary key words glucolipotoxicity • lipogenic genes • chromatin immunoprecipitation

Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; ChIP, chromatin immunoprecipitation; ChoRE, carbohydrate-responsive element; ChREBP, carbohydrate-responsive element binding protein; FAS, fatty acid synthase; L-PK, liver-type pyruvate kinase; PKA, protein kinase A; siRNA, small interfering RNA; SREBP-1c, sterol-responsive element binding protein-1c; TG, triglyceride; USF, upstream stimulatory factor

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