Peroxisome proliferator-activated receptor α (PPARα) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

Autor: A. Usardi, Francesca Frigerio, Clarissa Bartley, Thierry Brun, Domenico Bosco, Kim Ravnskjaer, Pierre Maechler, Susanne Mandrup
Rok vydání: 2009
Předmět:
CD36 Antigens
medicine.medical_specialty
Oleic Acid/ toxicity
Adenosine Triphosphate/metabolism
Endocrinology
Diabetes and Metabolism
Carbohydrates
Cell Culture Techniques
Peroxisome proliferator-activated receptor
Apoptosis
Fatty Acids
Nonesterified
Carbohydrate metabolism
Biology
Carbohydrates/ physiology
Carnitine O-Palmitoyltransferase/genetics
Fatty Acids
Nonesterified/pharmacology
Adenosine Triphosphate
Downregulation and upregulation
Tubulin
Insulin-Secreting Cells
Internal medicine
Insulin Secretion
Internal Medicine
medicine
Humans
Insulin
PPAR alpha
ddc:612
Insulin/secretion
chemistry.chemical_classification
ddc:617
Carnitine O-Palmitoyltransferase
Reverse Transcriptase Polymerase Chain Reaction
Apoptosis/drug effects
Fatty acid
Metabolism
Peroxisome
Glucose/pharmacology
Glucose
Endocrinology
Gene Expression Regulation
chemistry
Lipotoxicity
Insulin-Secreting Cells/cytology/drug effects/pathology/ physiology
PPAR alpha/pharmacology/ physiology
Antigens
CD36/genetics
Peroxisome proliferator-activated receptor alpha
Tubulin/genetics
Oleic Acid
Zdroj: Diabetologia, Vol. 53, No 2 (2010) pp. 331-340
Frigerio, F, Brun, T, Bartley, C, Usardi, A, Bosco, D, Ravnskjær, K, Mandrup, S & Maechler, P 2009, ' Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism ', Diabetologia, vol. 53, no. 2, pp. 331--340 . https://doi.org/10.1007/s00125-009-1590-6
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-009-1590-6
Popis: Udgivelsesdato: 2009 AIMS/HYPOTHESIS: Pancreatic beta cells chronically exposed to fatty acids may lose specific functions and even undergo apoptosis. Generally, lipotoxicity is triggered by saturated fatty acids, whereas unsaturated fatty acids induce lipodysfunction, the latter being characterised by elevated basal insulin release and impaired glucose responses. The peroxisome proliferator-activated receptor alpha (PPARalpha) has been proposed to play a protective role in this process, although the cellular mechanisms involved are unclear. METHODS: We modulated PPARalpha production in INS-1E beta cells and investigated key metabolic pathways and genes responsible for metabolism-secretion coupling during a culture period of 3 days in the presence of 0.4 mmol/l oleate. RESULTS: In INS-1E cells, the secretory dysfunction primarily induced by oleate was aggravated by silencing of PPARalpha. Conversely, PPARalpha upregulation preserved glucose-stimulated insulin secretion, essentially by increasing the response at a stimulatory concentration of glucose (15 mmol/l), a protection we also observed in human islets. The protective effect was associated with restored glucose oxidation rate and upregulation of the anaplerotic enzyme pyruvate carboxylase. PPARalpha overproduction increased both beta-oxidation and fatty acid storage in the form of neutral triacylglycerol, revealing overall induction of lipid metabolism. These observations were substantiated by expression levels of associated genes. CONCLUSIONS/INTERPRETATION: PPARalpha protected INS-1E beta cells from oleate-induced dysfunction, promoting both preservation of glucose metabolic pathways and fatty acid turnover.
Databáze: OpenAIRE
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