Activation of PPAR尾/未 protects pancreatic 尾 cells from palmitate-induced apoptosis by upregulating the expression of GLP-1 receptor

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• 作者：Yan Yang ; Yuzhen Tong ; Meng Gong ; Yanrong Lu ; Chengshi Wang ; Mingliang Zhou ; Qiu Yang ; Tingrui Mao ; Nanwei Tong
• 关键词：PPAR尾/未 ; peroxisome proliferator-activated receptor 尾/未 ; GLP-1R ; glucagon-like peptide-1 receptor ; GW ; GW501516 ; PA ; palmitate ; qPCR ; quantitative polymerase chain reaction ; SREBP-1c ; sterol regulatory element binding protein-1c ; GSIS ; glucose-stimulated insulin secretion ; T2D ; type 2 diabetes ; GPCR ; G protein coupled receptor ; KRBH ; glucose-free Krebs&ndash ; Ringer bicarbonate HEPES buffer ; ELISA ; enzyme-linked immunosorbent assay ; FDA ; fluorescein diacetate ; PI ; propidium iodide ; Ex ; exendi
• 刊名：Cellular Signalling
• 出版年：February, 2014
• 年：2014
• 卷：26
• 期：2
• 页码：268-278
• 全文大小：2678 K

文摘

We previously showed that activated peroxisome proliferator-activated receptor (PPAR)尾/未 can protect pancreatic 尾 cells against lipotoxic apoptosis. However, the molecular mechanism remained unclear. Glucagon-like peptide-1 receptor (GLP-1R) has been reported to exhibit a protective effect against lipotoxic apoptosis in pancreatic 尾 cells. In the present study, we aimed to investigate the underlying molecular mechanisms that PPAR尾/未 activation suppressed apoptosis and improved 尾 cell function impaired by fatty acids, focusing on contribution of GLP-1R. Isolated rat islets and rat insulin-secreting INS-1 cells were treated with the PPAR尾/未 agonist GW501516 (GW) in the presence or absence of palmitate (PA) and transfected with siRNA for PPAR尾/未 or treated with the PPAR尾/未 antagonist GSK0660. Apoptosis was assessed by DNA fragmentation, Hoechst 33342 staining and flow cytometry. GLP-1R expression in INS-1 cells and islets was assayed by immunoblotting, quantitative PCR (qPCR) and immunofluorescence staining. SREBP-1c, Caveolin-1, Akt, Bcl-2, Bcl-xl and caspase-3 expression was measured using immunoblotting and qPCR. Our results showed that PPAR尾/未 activation decreased apoptosis in 尾 cells and robustly stimulated GLP-1R expression under lipotoxic conditions. GW enhanced glucose-stimulated insulin secretion (GSIS) impaired by PA through stimulation of GLP-1R expression in 尾 cells. Moreover, SREBP-1c/Caveolin-1 signaling was involved in PPAR尾/未-regulated GLP-1R expression. Finally, GW exerted anti-apoptotic effects via interfering with GLP-1R-dependent Akt/Bcl-2 and Bcl-xl/caspase-3 signaling pathways. Our study suggested that the anti-apoptotic action of GW may involve its transcriptional regulation of GLP-1R, and PPAR尾/未 activation may represent a new therapeutic method for protecting pancreatic 尾 cells from lipotoxicity.