Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation.
Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation.
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葡萄糖型毒性通过TNFR5/CD40介导的STAT1和NF-κB激活引发胰腺β细胞死亡。
DOI：
10.1038/cddis.2016.203
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发表时间：
2016-08-11
影响因子：
9
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中科院分区：
文献类型：
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2型糖尿病是一种慢性代谢障碍，其中未能维持正常的葡萄糖稳态与肥胖和通常在这些患者中发现的伴随的游离脂肪酸浓度升高有关，并因肥胖和伴随的游离脂肪酸浓度升高而加剧。高脂血症和脂蛋白血症通过激活转录因子活化B细胞核因子κ轻链增强子（NF-κB）和信号转导子和转录激活子（STAT）-1共同导致胰岛素生成β细胞群下降。然而，有大量的分子可能能够调节NF-κB和STAT 1活性，并且目前尚不清楚糖脂毒性最初诱导NF-κB和STAT 1活化的机制。使用高密度微阵列分析β细胞转录组，我们已经确定了那些对葡萄糖和脂肪酸环境最敏感的基因和蛋白质。我们的数据显示，在那些可能能够激活STAT 1或NF-κB通路的细胞中，肿瘤坏死因子受体（TNFR）-5是被糖脂毒性上调最高的。重要的是，我们的数据还表明，TNFR 5的生理配体CD 40 L引发β细胞中的NF-κB活性，而TNFR 5的选择性敲低可改善STAT 1表达和NF-κB活性的糖脂毒性诱导。该数据首次表明TNFR 5信号传导在触发糖脂毒性胰岛细胞死亡中起主要作用。
Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis is associated with, and exacerbated by, obesity and the concomitant-elevated free fatty acid concentrations typically found in these patients. Hyperglycaemia and hyperlipidaemia together contribute to a decline in insulin-producing β-cell mass through activation of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-κB and STAT1 activation is currently poorly defined. Using high-density microarray analysis of the β-cell transcritptome, we have identified those genes and proteins most sensitive to glucose and fatty acid environment. Our data show that of those potentially able to activate STAT1 or NF-κB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in β-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.
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