Peroxisome proliferator-activated receptor α (PPARα) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism
Peroxisome proliferator-activated receptor α (PPARα) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism
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DOI：
10.1007/s00125-009-1590-6
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发表时间：
2010-02-01
期刊：
影响因子：
8.2
通讯作者：
Maechler, P.
中科院分区：
文献类型：
--
作者：
Frigerio, F.;Brun, T.;Maechler, P.
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 (PPAR alpha) has been proposed to play a protective role in this process, although the cellular mechanisms involved are unclear.We modulated PPAR alpha 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.In INS-1E cells, the secretory dysfunction primarily induced by oleate was aggravated by silencing of PPAR alpha. Conversely, PPAR alpha 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. PPAR alpha 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.PPAR alpha protected INS-1E beta cells from oleate-induced dysfunction, promoting both preservation of glucose metabolic pathways and fatty acid turnover.
