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首页> 外文期刊>Cellular Physiology and Biochemistry >Palmitate-induced inhibition of insulin gene expression in rat islet β-cells involves the ceramide transport protein
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Palmitate-induced inhibition of insulin gene expression in rat islet β-cells involves the ceramide transport protein

机译:棕榈酸酯诱导的对大鼠胰岛β细胞胰岛素基因表达的抑制作用涉及神经酰胺转运蛋白

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Endogenous ceramide plays an important role in the palmitate (Palm) impairment of proinsulin gene expression in pancreatic islet β-cells. Changes in the liposoluble ceramide levels not only depend on metabolic enzymes but also on its transport to subcellular sites in response to Palm stimuli. In this study, we show that suppression of ceramide transport protein (CERT) mRNA with small interfering RNA contributed to intracellular ceramide accumulation in response to chronic Palm exposure and impairment of proinsulin gene expression, similar to the effect of inhibiting ceramide scavenging enzyme sphingomyelin synthase (SMS). High dose Palm treatment increased protein kinase D (PKD)-induced phosphorylation of CERT and its dysfunction. Intracellular accumulation of ceramide was associated with reduction of PDX-1 nuclear localization and MafA protein levels and stimulation of CCAAT/enhancer binding protein β (C/EBP β) expression. These conditions also corresponded with a reduction of PDX-1 and MafA and an increase of C/EBP β binding to the insulin promoter. Furthermore, down-regulation of C/EBP β could block ceramide impairment of proinsulin gene expression. The results reveal that Palm-mediated dysfunction of ceramide transport may contribute to intracellular ceramide accumulation and result in dysfunction of pancreatic beta cells by affecting binding of transcription factors to the insulin promoter.
机译:内源性神经酰胺在胰岛β细胞中胰岛素原基因表达的棕榈酸酯(Palm)损伤中起重要作用。脂溶性神经酰胺水平的变化不仅取决于代谢酶,还取决于其对Palm刺激物向亚细胞部位的转运。在这项研究中,我们显示了通过抑制小分子干扰RNA抑制神经酰胺转运蛋白(CERT)mRNA有助于响​​应慢性手掌暴露和胰岛素原基因表达受损的细胞内神经酰胺蓄积,类似于抑制神经酰胺清除酶鞘磷脂合酶的作用(短信)。高剂量Palm治疗可增加蛋白激酶D(PKD)诱导的CERT磷酸化及其功能障碍。细胞内神经酰胺的积聚与PDX-1核定位和MafA蛋白水平的降低以及CCAAT /增强子结合蛋白β(C / EBPβ)表达的刺激有关。这些条件还对应于PDX-1和MafA的减少和与胰岛素启动子的C / EBPβ结合的增加。此外,C / EBPβ的下调可以阻止神经酰胺损伤胰岛素原基因表达。结果表明,Palm介导的神经酰胺转运功能障碍可能会影响细胞内神经酰胺的积累,并通过影响转录因子与胰岛素启动子的结合而导致胰腺β细胞功能障碍。

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