The Transcription Factor SREBP-1c Is Instrumental in the Development of औ-Cell Dysfunction
| Autor: | Peter A. Antinozzi, Haiyan Wang, Pierre Maechler, Anneli Björklund, Kerstin A. Hagenfeldt-Johansson, Laura Herrero, Claes B. Wollheim |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
medicine.medical_treatment Cell Carbohydrate metabolism Biology Biochemistry Islets of Langerhans Internal medicine Lipid biosynthesis Lipid droplet Gene expression medicine Animals Hypoglycemic Agents Insulin Molecular Biology Transcription factor Cell growth Cell Biology Clone Cells Rats DNA-Binding Proteins Glucose medicine.anatomical_structure Endocrinology Diabetes Mellitus Type 2 Gene Expression Regulation CCAAT-Enhancer-Binding Proteins lipids (amino acids peptides and proteins) Sterol Regulatory Element Binding Protein 1 Protein Processing Post-Translational Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 278:16622-16629 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m212488200 |
| Popis: | Accumulation of lipids in non-adipose tissues is often associated with Type 2 diabetes and its complications. Elevated expression of the lipogenic transcription factor, sterol regulatory element binding protein-1c (SREBP-1c), has been demonstrated in islets and liver of diabetic animals. To elucidate the molecular mechanisms underlying SREBP-1c-induced beta-cell dysfunction, we employed the Tet-On inducible system to achieve tightly controlled and conditional expression of the nuclear active form of SREBP-1c (naSREBP-1c) in INS-1 cells. Controlled expression of naSREBP-1c induced massive accumulation of lipid droplets and blunted nutrient-stimulated insulin secretion in INS-1 cells. K(+)-evoked insulin exocytosis was unaltered. Quantification of the gene expression profile in this INS-1 stable clone revealed that naSREBP-1c induced beta-cell dysfunction by targeting multiple genes dedicated to carbohydrate metabolism, lipid biosynthesis, cell growth, and apoptosis. naSREBP-1c elicits cell growth-arrest and eventually apoptosis. We also found that the SREBP-1c processing in beta-cells was irresponsive to acute stimulation of glucose and insulin, which was distinct from that in lipogenic tissues. However, 2-day exposure to these agents promoted SREBP-1c processing. Therefore, the SREBP-1c maturation could be implicated in the pathogenesis of beta-cell glucolipotoxicity. |
| Databáze: | OpenAIRE |
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