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首页> 外文期刊>Life sciences >Sequential activation of caspases and synergistic beta-cell cytotoxicity by palmitate and anti-Fas antibodies.
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Sequential activation of caspases and synergistic beta-cell cytotoxicity by palmitate and anti-Fas antibodies.

机译：棕榈酸酯和抗Fas抗体顺序激活半胱氨酸蛋白酶和协同作用的β细胞毒性。

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To assess the mechanism of beta-cell lipotoxicity in comparison with Fas-mediated cell death, we used a mouse beta-cell clone stably transfected with human Fas. Palmitate induced beta-cell death in correlation with medium glucose levels between 5 and 20 mmol/l, while Fas-mediated cytotoxicity was observed irrespective of glucose concentration. At the glucose level of 10 mmol/l, palmitate induced caspase-6 activity within 3 h, and caspase-3 activity after a lag period of 6 h. The activities of caspases were correlated with glucose concentration. A caspase-6 inhibitor attenuated caspase-3 activation and cell death induced by palmitate. Oxfenicine, an inhibitor of carnitine palmitoyltransferase-1, attenuated both palmitate-induced cytotoxicity and activation of caspases. Finally, beta-cell cytotoxicity caused by the combination of anti-Fas and palmitate at 25 mmol/l of glucose was greater than the sum of those induced by each. These observations suggest that palmitate induces sequential activation of caspase-6 and caspase-3 through a mitochondrial signal(s), and caspase-6 plays a primary role in the mechanism. Fas-mediated beta-cell death and lipotoxicity may share common mechanisms involving caspase activation, and thereby synergistically inducing beta-cell death, although upstream signaling pathways are distinct.
机译：为了评估与Fas介导的细胞死亡相比，β细胞脂毒性的机制，我们使用了稳定转染了人类Fas的小鼠β细胞克隆。棕榈酸酯诱导的β细胞死亡与中等葡萄糖水平在5至20 mmol / l之间相关，而无论葡萄糖浓度如何，均观察到Fas介导的细胞毒性。在葡萄糖水平为10 mmol / l时，棕榈酸酯在3 h内诱导caspase-6活性，在6 h滞后后诱导caspase-3活性。半胱天冬酶的活性与葡萄糖浓度相关。 caspase-6抑制剂减弱了棕榈酸酯诱导的caspase-3活化和细胞死亡。奥昔芬尼是肉碱棕榈酰转移酶-1的抑制剂，可减弱棕榈酸酯诱导的细胞毒性和胱天蛋白酶的激活。最后，在25 mmol / l葡萄糖下，抗-Fas和棕榈酸酯的组合所引起的β细胞细胞毒性大于两者各自诱导的总和。这些观察结果表明棕榈酸酯通过线粒体信号诱导caspase-6和caspase-3的顺序激活，而caspase-6在该机制中起主要作用。 Fas介导的β细胞死亡和脂毒性可能共享涉及caspase激活的共同机制，从而协同诱导β细胞死亡，尽管上游信号传导途径是截然不同的。

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