Glucose Down-regulates the Expression of the Peroxisome Proliferator-activated Receptor-α Gene in the Pancreatic β-Cell

• Published in: The Journal of biological chemistry 2000-11, Vol.275 (46), p.35799-35806
• Main Authors: Roduit, Raphaël, Morin, Johane, Massé, Frédéric, Segall, Laura, Roche, Enrique, Newgard, Christopher B., Assimacopoulos-Jeannet, Françoise, Prentki, Marc
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Glucose - analogs & derivatives; Glucose - metabolism; Glucose - pharmacology; hyperglycemia; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Kinetics; Malonyl Coenzyme A - metabolism; malonyl-CoA; Models, Biological; Oleic Acid - metabolism; Oleic Acid - pharmacology; Oxidation-Reduction - drug effects; Palmitic Acid - metabolism; peroxisome proliferator-activated receptors; Protein Binding - drug effects; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Response Elements - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Triglycerides - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M006001200

To better understand the action of glucose on fatty acid metabolism in the β-cell and the link between chronically elevated glucose or fatty acids and β-cell decompensation in adipogenic diabetes, we investigated whether glucose regulates peroxisomal proliferator-activated receptor (PPAR) gene expression in the β-cell. Islets or INS(832/13) β-cells exposed to high glucose show a 60–80% reduction in PPARα 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 PPARα 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 PPARα gene expression together with a rise in malonyl-CoA plays a role in the coordinated adaptation of β-cell glucose and lipid metabolism to hyperglycemia and may be implicated in the mechanism of β-cell “glucolipotoxicity.”