Proceedings of the National Academy of Sciences - PNAS, 2012-02, Vol.109 (7), p.2376-2381
2012
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- Autor(en) / Beteiligte
- Titel
- Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2012-02, Vol.109 (7), p.2376-2381
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The G protein-coupled free fatty acid receptor-1 (FFA1/GPR40) plays a major role in the regulation of insulin secretion by fatty acids. GPR40 is considered a potential therapeutic target to enhance insulin secretion in type 2 diabetes; however, its mode of regulation is essentially unknown. The aims of this study were to test the hypothesis that glucose regulates GPR40 gene expression in pancreatic β-cells and to determine the mechanisms of this regulation. We observed that glucose stimulates GPR40 gene transcription in pancreatic β-cells via increased binding of pancreas-duodenum homeobox-1 (Pdx-1) to the A-box in the HR2 region of the GPR40 promoter. Mutation of the Pdx-1 binding site within the HR2 abolishes glucose activation of GPR40 promoter activity. The stimulation of GPR40 expression and Pdx-1 binding to the HR2 in response to glucose are mimicked by N-acetyl glucosamine, an intermediate of the hexosamine biosynthesis pathway, and involve PI3K-dependent O-GlcNAcylation of Pdx-1 in the nucleus. We demonstrate that O-GlcNAc transferase (OGT) interacts with the product of the PI3K reaction, phosphatidylinositol 3,4,5-trisphosphate (PIP3), in the nucleus. This interaction enables OGT to catalyze O-GlcNAcylation of nuclear proteins, including Pdx-1. We conclude that glucose stimulates GPR40 gene expression at the transcriptional level through Pdx-1 binding to the HR2 region and via a signaling cascade that involves an interaction between OGT and PIP3 at the nuclear membrane. These observations reveal a unique mechanism by which glucose metabolism regulates the function of transcription factors in the nucleus to induce gene expression.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1114350109Titel-ID: cdi_proquest_journals_922053505
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Acetylglucosamine - metabolism, Animals, Beta cells, binding sites, Biological Sciences, biosynthesis, Diabetes mellitus, Duodenum - metabolism, Fatty acids, free fatty acids, Gene expression, Glucosamine, Glucose, Glucose - metabolism, Hexosamines - biosynthesis, Homeodomain Proteins - metabolism, Humans, Insulin, Insulin - metabolism, Insulin Secretion, islets of Langerhans, Mice, Mice, Inbred C57BL, Mutation, noninsulin-dependent diabetes mellitus, nuclear membrane, Nuclear membranes, nuclear proteins, Nuclei, Pancreas, Pancreas - metabolism, phosphatidylinositol 3,4,5-triphosphate, phosphatidylinositol 3-kinase, Phosphatidylinositol 3-Kinases - metabolism, Promoters, Proteins, Receptors, G-Protein-Coupled - genetics, Secretion, Signal transduction, Transcription, transcription (genetics), Transcription factors, Transcription, Genetic