ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells
| Autor: | Francesca Frigerio, Søren Fisker Schmidt, Lars la Cour Poulsen, Pierre Maechler, Michael Boergesen, Susanne Mandrup |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Exons/physiology
Transcription Genetic Peroxisome proliferator-activated receptor Transcription Factors/genetics/metabolism Biochemistry Mice 0302 clinical medicine Insulin-Secreting Cells Gene expression Sweetening Agents/metabolism/pharmacology Repressor Proteins/genetics/metabolism Transcription Genetic/drug effects/physiology chemistry.chemical_classification Regulation of gene expression 0303 health sciences Gene knockdown Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Fatty Acids Fatty Acids/genetics/metabolism Nuclear Proteins Exons 3. Good health medicine.anatomical_structure Gene Knockdown Techniques Insulin-Secreting Cells/cytology/metabolism Oxidation-Reduction medicine.medical_specialty 030209 endocrinology & metabolism Biology Carbohydrate metabolism 03 medical and health sciences Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism Cell Line Tumor Internal medicine medicine Animals Humans Nuclear Proteins/genetics/metabolism Gene Regulation PPAR alpha Gene Expression Regulation/drug effects/physiology Rats Wistar ddc:612 Carbohydrate-responsive element-binding protein Molecular Biology Transcription factor 030304 developmental biology Pancreatic islets Cell Biology Protein Structure Tertiary Rats Repressor Proteins Glucose HEK293 Cells Endocrinology Gene Expression Regulation chemistry Sweetening Agents Glucose/metabolism/pharmacology PPAR alpha/biosynthesis/genetics Transcription Factors |
| Zdroj: | The Journal of biological chemistry Boergesen, M, Poulsen, L L C, Schmidt, S F, Frigerio, F, Maechler, P & Mandrup, S 2011, ' ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor {alpha} Expression in Pancreatic {beta}-Cells ', Journal of Biological Chemistry, vol. 286, no. 15, pp. 13214-13225 . https://doi.org/10.1074/jbc.M110.215467 Journal of Biological Chemistry, Vol. 286, No 15 (2011) pp. 13214-25 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.M110.215467 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|