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首页> 外文期刊>Cell death and differentiation >JunB protects β-cells from lipotoxicity via the XBP1-AKT pathway
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JunB protects β-cells from lipotoxicity via the XBP1-AKT pathway

机译：JunB通过XBP1-AKT途径保护β细胞免于脂毒性

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Diets rich in saturated fats may contribute to the loss of pancreatic β-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes β-cell survival and mediates part of the beneficial effects of GLP-1 agonists. In this study we interrogated the molecular mechanisms involved in JunB-mediated β-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to β-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient β-cells identified a gene expression signature of a downregulated endoplasmic reticulum (ER) stress response and inhibited AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBPδ during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important antiapoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic β-cell death potentiated by JunB siRNA. Interestingly, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to β-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to β-cell apoptosis. In conclusion, JunB modulates the β-cell ER stress response and AKT signaling via the induction of XBP1s. The activation of the JunB gene network and the crosstalk between the ER stress and AKT pathway constitute a crucial defense mechanism by which GLP-1 agonists protect against lipotoxic β-cell death. These findings elucidate novel β-cell-protective signal transduction in type 2 diabetes.
机译：在2型糖尿病中，富含饱和脂肪的饮食可能会导致胰腺β细胞的损失。 JunB是激活蛋白1（AP-1）转录因子家族的成员，可促进β细胞存活并介导GLP-1激动剂的部分有益作用。在这项研究中，我们询问了涉及JunB介导的β细胞保护免于脂毒性的分子机制。饱和脂肪酸棕榈酸酯降低了JunB的表达，这种损失可能导致β细胞凋亡，因为JunB的过表达保护了细胞免受脂毒性。缺乏JunB的β细胞的阵列分析确定了下调的内质网（ER）应激反应的基因表达特征，并抑制了AKT信号传导。在内质网应激期间，JunB通过转录因子c /EBPδ刺激XBP1表达，而XBP1s的强制表达挽救了JunB缺陷细胞的生存能力，构成了重要的抗凋亡机制。 JunB沉默抑制AKT激活并通过其去磷酸化激活促凋亡的Bcl-2蛋白BAD。 BAD敲低逆转了由JunB siRNA增强的脂毒性β细胞死亡。有趣的是，XBP1链接JunB和AKT信号，因为XBP1敲低还减少了AKT磷酸化。 GLP-1激动剂诱导cAMP依赖性AKT磷酸化，从而导致β细胞保护棕榈酸酯诱导的细胞凋亡。 JunB和XBP1敲低或IRE1抑制降低了cAMP的AKT激活，从而导致β细胞凋亡。总之，JunB通过诱导XBP1s调节β细胞ER应激反应和AKT信号传导。 JunB基因网络的激活以及内质网应激与AKT途径之间的串扰构成了至关重要的防御机制，GLP-1激动剂可通过该防御机制防御脂毒性β细胞死亡。这些发现阐明了2型糖尿病中新型的β细胞保护信号转导。

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