Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction
| Autor: | Christian Widmann, Amar Abderrahmani, Sonia Gattesco, Pascal Lovis, E. Roggli, Jiang-Yan Yang, D. Ross Laybutt, Romano Regazzi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Vesicle-Associated Membrane Protein 2 Endocrinology Diabetes and Metabolism medicine.medical_treatment Cell Blotting Western Palmitates Gene Expression Apoptosis Biology Cell Line 03 medical and health sciences Islets of Langerhans Mice 0302 clinical medicine Internal medicine Insulin-Secreting Cells Gene expression microRNA Internal Medicine medicine Animals Insulin Secretion 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Reverse Transcriptase Polymerase Chain Reaction Pancreatic islets Fatty Acids MicroRNAs medicine.anatomical_structure Endocrinology Islet Studies Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Signal Transduction Signal transduction |
| Zdroj: | Diabetes Diabetes, vol. 57, no. 10, pp. 2728-2736 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE—Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic β-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation. RESEARCH DESIGN AND METHODS—We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis. RESULTS—Prolonged exposure of the β-cell line MIN6B1 and pancreatic islets to palmitate causes a time- and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in β-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion. CONCLUSIONS—Our findings suggest that at least part of the detrimental effects of palmitate on β-cells is caused by alterations in the level of specific miRNAs. |
| Databáze: | OpenAIRE |
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