Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis
Loss of Egr-1 sensitizes pancreatic β-cells to palmitate-induced ER stress and apoptosis
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DOI：
10.1007/s00109-015-1272-4
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发表时间：
2015-07-01
影响因子：
4.7
通讯作者：
Tsai, Yau-Sheng
中科院分区：
文献类型：
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作者：
Cheong, Mun-Wai;Kuo, Li-Hua;Tsai, Yau-Sheng
胰腺β细胞对脂肪酸诱导的内质网（ER）应激和凋亡特别敏感。为了了解β细胞如何感知脂肪酸刺激并转化为长期适应性反应，我们研究了棕榈酸（PA）是否调节早期生长反应-1（Egr-1），这是一种立即早期转录因子，由许多环境刺激诱导并与细胞增殖，分化和凋亡有关。我们发现PA能快速、瞬时地诱导MIN 6胰岛素瘤细胞Egr-1表达，并伴有钙离子内流和ERK 1/2磷酸化。钙螯合和MEK 1/2抑制阻断PA诱导的Egr-1上调，表明PA通过钙流入-MEK 1/2-ERK 1/2级联诱导Egr-1表达。敲低Egr-1可增加PA诱导的caspase-3活化和ER应激标志物，并降低PA诱导的Akt磷酸化和胰岛素分泌及信号传导。Akt补充和胰岛素补充挽救PA诱导的Egr-1敲低细胞凋亡。这些结果表明，缺乏Egr-1失去了其耦合短期胰岛素/Akt途径的长期生存适应的能力。最后，Egr-1缺陷的小鼠胰岛更容易受到离体刺激的细胞凋亡。在人胰腺组织中，EGFR 1的表达与ER应激标志物和抗凋亡基因的表达相关。总之，Egr-1是由PA诱导的，并进一步试图通过改善胰岛素/Akt信号转导来拯救β细胞免于ER应激和凋亡。我们的研究强调了Egr-1作为胰腺β细胞中将脂肪酸刺激转化为细胞适应机制的关键早期传感器。
Pancreatic beta-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how beta-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue beta-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic beta-cells to translate fatty acid stimuli into a cellular adaptation mechanism.