Protective Role of PPARdelta in Lipoapoptosis of Pancreatic beta Cells
Protective Role of PPARdelta in Lipoapoptosis of Pancreatic beta Cells
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PPARδ 在胰腺 β 细胞脂肪凋亡中的保护作用
DOI：
10.1007/s11745-016-4190-5
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发表时间：
2016
期刊：
影响因子：
1.9
通讯作者：
Tong Nanwei
中科院分区：
文献类型：
--
作者：
Yang Yan;Ren Jiangong;Tong Yuzhen;Hu Xuejian;Lv Qingguo;Tong Nanwei
脂细胞凋亡在2型糖尿病的发病机制中起着重要作用。过氧化物酶体增殖物激活受体增量(PPARDelta)是糖脂代谢的重要调节因子，可减轻糖尿病患者由脂肪酸诱导的胰腺β细胞的脂毒性。然而，这一过程背后的详细分子机制尚不完全清楚。在本研究中，我们研究了PPARDelta的激活对棕榈酸酯诱导的β细胞凋亡的影响，并探讨了其抗凋亡作用的潜在机制。用DNA片段分析和Hoechst 33342染色检测细胞的凋亡率。用Western blotting、聚合酶链式反应定量检测胰升糖素样肽-1受体(GLP-1R)在INS-1细胞中的表达，并用免疫荧光染色进一步证实。用染色质免疫沉淀法测定PPARDelta与GLP-1R基因中同源PPRE的相互作用。我们的结果显示，INS-1细胞在棕榈酸酯作用24小时后，细胞凋亡率显著增加，GW501516可抑制这种作用。PPARDelta通过PI3K/PKB/FoxO1信号通路在胰腺β细胞中发挥抗凋亡作用。此外，在脂毒条件下，PPARDelta上调了GLP-1R的表达。芯片分析显示，在INS-1细胞中，PPARDelta与GLP-1R基因的非规范PPRE基序直接结合。我们的研究提示，PPARDelta的抗细胞凋亡作用可能与其对GLP-1R和PI3/K/PKB/FoxO1信号的转录调控有关。GW501516和其他可能的基于GW的策略可能会带来改善血糖控制之外的额外好处。
Lipoapoptosis plays an important role in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor delta (PPARdelta), a vital regulator of glucose and lipid metabolism, may reduce fatty acid-induced pancreatic β cell lipotoxicity in diabetes. However, the detailed molecular mechanisms underlying this process are not fully understood. In this study, we investigated the effect of activation of PPARdelta on palmitate-induced β cell apoptosis, and we explored the potential mechanism of the antiapoptotic effect. The cell apoptosis was determined by DNA fragmentation analysis and Hoechst 33342 staining. The expressing of glucagon-like peptide-1 receptor (GLP-1R) in INS-1 cells was assessed by Western blotting, quantification of PCR, and was further confirmed by immunofluorescence staining. The potential of PPARdelta to interact with homologous PPRE in the GLP-1R gene was determined by Chromatin immunoprecipitation (ChIP). Our results showed that exposure of INS-1 cells to palmitate for 24 h caused a significant increase in cell apoptosis, which was inhibited by GW501516. PPARdelta exerted anti-apoptotic effects in pancreatic β cells via the PI3 K/PKB/FoxO1 signaling pathway. Moreover, PPARdelta upregulated the GLP-1R expression under lipotoxic conditions. The ChIP assay revealed a direct binding of PPARdelta to a noncanonical PPRE motif of the GLP-1R gene in INS-1 cells. Our study suggested that the anti-apoptotic action of PPARdelta may involve its transcriptional regulation of GLP-1R and PI3 K/PKB/FoxO1 signaling. GW501516 and possible other GW-based strategies may confer additional benefit beyond improved glycemic control.