Glucose down-regulates the expression of the peroxisome proliferator-activated receptor-alpha gene in the pancreatic beta -cell
| Autor: | Raphaël Roduit, Marc Prentki, Enrique Roche, Laura Segall, Françoise Assimacopoulos-Jeannet, Johane Morin, Frédéric Massé, Christopher B. Newgard |
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| Rok vydání: | 2000 |
| Předmět: |
Snf3
medicine.medical_specialty Palmitic Acid Peroxisome proliferator-activated receptor Down-Regulation Receptors Cytoplasmic and Nuclear Biology Response Elements Biochemistry Models Biological chemistry.chemical_compound Islets of Langerhans Internal medicine Gene expression Insulin Secretion medicine Animals Insulin RNA Messenger Rats Wistar Molecular Biology Cells Cultured Triglycerides chemistry.chemical_classification Fatty acid metabolism Dose-Response Relationship Drug Fatty acid Lipid metabolism Cell Biology Peroxisome Rats DNA-Binding Proteins Malonyl Coenzyme A Kinetics Endocrinology Glucose chemistry Mannoheptulose Oxidation-Reduction Oleic Acid Protein Binding Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 275(46) |
| ISSN: | 0021-9258 |
| Popis: | To better understand the action of glucose on fatty acid metabolism in the beta-cell and the link between chronically elevated glucose or fatty acids and beta-cell decompensation in adipogenic diabetes, we investigated whether glucose regulates peroxisomal proliferator-activated receptor (PPAR) gene expression in the beta-cell. Islets or INS(832/13) beta-cells exposed to high glucose show a 60-80% reduction in PPARalpha mRNA expression. Oleate, either in the absence or presence of glucose, has no effect. The action of glucose is dose-dependent in the 6-20 mm range and maximal after 6 h. Glucose also causes quantitatively similar reductions in PPARalpha protein and DNA binding activity of this transcription factor. The effect of glucose is blocked by the glucokinase inhibitor mannoheptulose, is partially mimicked by 2-deoxyglucose, and is not blocked by the 3-O-methyl or the 6-deoxy analogues of the sugar that are not phosphorylated. Chronic elevated glucose reduces the expression levels of the PPAR target genes, uncoupling protein 2 and acyl-CoA oxidase, which are involved in fat oxidation and lipid detoxification. A 3-day exposure of INS-1 cells to elevated glucose results in a permanent rise in malonyl-CoA, the inhibition of fat oxidation, and the promotion of fatty acid esterification processes and causes elevated insulin secretion at low glucose. The results suggest that a reduction in PPARalpha gene expression together with a rise in malonyl-CoA plays a role in the coordinated adaptation of beta-cell glucose and lipid metabolism to hyperglycemia and may be implicated in the mechanism of beta-cell "glucolipotoxicity." |
| Databáze: | OpenAIRE |
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