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Title

Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism
Authors
Frigerio, Francesca
Brun, Thierry
Bartley, C.
Usardi, A.
Bosco, Domenico
Ravnskjaer, K.
Mandrup, S.
Maechler, Pierre
Published in Diabetologia. 2010, vol. 53, no. 2, p. 331-340
Abstract 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.
Keywords Adenosine Triphosphate/metabolism — Antigens, CD36/genetics — Apoptosis/drug effects — Carbohydrates/ physiology — Carnitine O-Palmitoyltransferase/genetics — Cell Culture Techniques — Fatty Acids, Nonesterified/pharmacology — Gene Expression Regulation — Glucose/pharmacology — Humans — Insulin/secretion — Insulin-Secreting Cells/cytology/drug effects/pathology/ physiology — Oleic Acid/ toxicity — PPAR alpha/pharmacology/ physiology — Reverse Transcriptase Polymerase Chain Reaction — Tubulin/genetics
Identifiers
PMID: 19908022
Full text
Article - document accessible for UNIGE members only Limited access to UNIGE
Other version: http://www.springerlink.com/content/100410/
Structures
Faculté de médecine / Section de médecine clinique / Département de chirurgie
Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme
Research groups Chirurgie viscérale (104)
Mitochondries et sécrétion d'insuline (671)
Citation
(ISO format) 		FRIGERIO, Francesca et al. Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism. In: Diabetologia, 2010, vol. 53, n° 2, p. 331-340. https://archive-ouverte.unige.ch/unige:20682

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Deposited on : 2012-05-23

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