J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M600289-JLR200 on August 4, 2006

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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 Xavier1,{dagger}, Guy A. Rutter1,{dagger}, Frédérique Diraison*, Chrysovalantis Andreolas* and Isabelle Leclerc2,{dagger}

* From the Henry Wellcome Laboratories for Integrated Cell Signalling, Department of Biochemistry, University of Bristol, Bristol, BS8 1TD
{dagger} 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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