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Title

ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells
Authors
Boergesen, Michael
Poulsen, Lars la Cour
Schmidt, Søren Fisker
Frigerio, Francesca
Maechler, Pierre
Mandrup, Susanne
Published in Journal of Biological Chemistry. 2011, vol. 286, no. 15, p. 13214-25
Abstract Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic β-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor α (PPARα) is an important regulator of genes involved in fatty acid metabolism and has been shown to protect against lipid-induced β-cell dysfunction. We and others have previously shown that expression of the PPARα gene in β-cells is rapidly repressed by glucose. Here we show that the PPARα gene is transcribed from five alternative transcription start sites, resulting in three alternative first exons that are spliced to exon 2. Expression of all PPARα transcripts is repressed by glucose both in insulinoma cells and in isolated pancreatic islets. The observation that the dynamics of glucose repression of PPARα transcription are very similar to those of glucose activation of target genes by the carbohydrate response element-binding protein (ChREBP) prompted us to investigate the potential role of ChREBP in the regulation of PPARα expression. We show that a constitutively active ChREBP lacking the N-terminal domain efficiently represses PPARα expression in insulinoma cells and in rodent and human islets. In addition, we demonstrate that siRNA-mediated knockdown of ChREBP abrogates glucose repression of PPARα expression as well as induction of well established ChREBP target genes in insulinoma cells. In conclusion, this work shows that ChREBP is a critical and direct mediator of glucose repression of PPARα gene expression in pancreatic β-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of β-cells.
Keywords Animals — Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism — Cell Line, Tumor — Exons/physiology — Fatty Acids/genetics/metabolism — Gene Expression Regulation/drug effects/physiology — Gene Knockdown Techniques — Glucose/metabolism/pharmacology — HEK293 Cells — Humans — Insulin-Secreting Cells/cytology/metabolism — Mice — Nuclear Proteins/genetics/metabolism — Oxidation-Reduction — PPAR alpha/biosynthesis/genetics — Protein Structure, Tertiary — Rats — Rats, Wistar — Repressor Proteins/genetics/metabolism — Sweetening Agents/metabolism/pharmacology — Transcription Factors/genetics/metabolism — Transcription, Genetic/drug effects/physiology
Identifiers
PMID: 21282101
Full text
Article (Published version) (1.2 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme
Research group Mitochondries et sécrétion d'insuline (671)
Citation
(ISO format) 		BOERGESEN, Michael et al. ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells. In: Journal of Biological Chemistry, 2011, vol. 286, n° 15, p. 13214-25. https://archive-ouverte.unige.ch/unige:25320

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Deposited on : 2013-01-10

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