Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)
| Autor: | Laura E. Parton, Frédérique Diraison, Pascal Ferré, Fabienne Foufelle, Isabelle Leclerc, Guy A. Rutter, Celia P. Briscoe |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Genetic Vectors Gene Expression Apoptosis Biochemistry Adenoviridae Islets of Langerhans Acetyltransferases Transduction Genetic Internal medicine medicine Animals Insulin Rats Wistar Molecular Biology Cells Cultured Triglycerides geography geography.geographical_feature_category biology Glucokinase Pancreatic islets Glucose transporter AMPK Cell Biology Ribonucleotides Aminoimidazole Carboxamide Islet Lipids Rats Insulin oscillation DNA-Binding Proteins Glucose Endocrinology medicine.anatomical_structure CCAAT-Enhancer-Binding Proteins biology.protein GLUT2 Fatty Acid Synthases Sterol Regulatory Element Binding Protein 1 Research Article Transcription Factors |
| Zdroj: | Biochemical Journal. 378:769-778 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj20031277 |
| Popis: | Accumulation of intracellular lipid by pancreatic islet β-cells has been proposed to inhibit normal glucose-regulated insulin secretion (‘glucolipotoxicity’). In the present study, we determine whether over-expression in rat islets of the lipogenic transcription factor SREBP1c (sterol-regulatory-element-binding protein-1c) affects insulin release, and whether changes in islet lipid content may be reversed by activation of AMPK (AMP-activated protein kinase). Infection with an adenovirus encoding the constitutively active nuclear fragment of SREBP1c resulted in expression of the protein in approx. 20% of islet cell nuclei, with a preference for β-cells at the islet periphery. Real-time PCR (TaqMan®) analysis showed that SREBP1c up-regulated the expression of FAS (fatty acid synthase; 6-fold), acetyl-CoA carboxylase-1 (2-fold), as well as peroxisomal-proliferator-activated receptor-γ (7-fold), uncoupling protein-2 (1.4-fold) and Bcl2 (B-cell lymphocytic-leukaemia proto-oncogene 2; 1.3-fold). By contrast, levels of pre-proinsulin, pancreatic duodenal homeobox-1, glucokinase and GLUT2 (glucose transporter isoform-2) mRNAs were unaltered. SREBP1c-transduced islets displayed a 3-fold increase in triacylglycerol content, decreased glucose oxidation and ATP levels, and a profound inhibition of glucose-, but not depolarisation-, induced insulin secretion. Culture of islets with the AMPK activator 5-amino-4-imidazolecarboxamide riboside decreased the expression of the endogenous SREBP1c and FAS genes, and reversed the effect of over-expressing active SREBP1c on FAS mRNA levels and cellular triacylglycerol content. We conclude that SREBP1c over-expression, even when confined to a subset of β-cells, leads to defective insulin secretion from islets and may contribute to some forms of Type II diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|