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ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells

Boergesen, Michael
Poulsen, Lars la Cour
Schmidt, Søren Fisker
Mandrup, Susanne
Published in The 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 AnimalsBasic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolismCell Line, TumorExons/physiologyFatty Acids/genetics/metabolismGene Expression Regulation/drug effects/physiologyGene Knockdown TechniquesGlucose/metabolism/pharmacologyHEK293 CellsHumansInsulin-Secreting Cells/cytology/metabolismMiceNuclear Proteins/genetics/metabolismOxidation-ReductionPPAR alpha/biosynthesis/geneticsProtein Structure, TertiaryRatsRats, WistarRepressor Proteins/genetics/metabolismSweetening Agents/metabolism/pharmacologyTranscription Factors/genetics/metabolismTranscription, Genetic/drug effects/physiology
PMID: 21282101
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Research group Mitochondries et métabolisme énergétique (671)
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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. doi: 10.1074/jbc.M110.215467 https://archive-ouverte.unige.ch/unige:25320

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Deposited on : 2013-01-10

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