Platelet-type 12-lipoxygenase deletion provokes a compensatory 12/15-lipoxygenase increase that exacerbates oxidative stress in mouse islet cells
Platelet-type 12-lipoxygenase deletion provokes a compensatory 12/15-lipoxygenase increase that exacerbates oxidative stress in mouse islet cells
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DOI：
10.1074/jbc.ra118.007102
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发表时间：
2019-04-19
影响因子：
4.8
通讯作者：
Linnemann, Amelia K.
中科院分区：
文献类型：
--
作者：
Conteh, Abass M.;Reissaus, Christopher A.;Linnemann, Amelia K.
在1型糖尿病中，自身免疫事件增加胰岛细胞中的氧化应激，引起细胞功能障碍和细胞凋亡。脂氧合酶是催化多不饱和脂肪酸氧化的酶，所述多不饱和脂肪酸可以形成参与多种生物功能（包括氧化应激）的脂质代谢物。12-脂氧合酶和12/15-脂氧合酶是在胰岛中表达的相关但不同的酶，但它们对这些区域氧化应激的相对贡献仍在阐明中。在这项研究中，我们使用了编码12-脂氧合酶（花生四烯酸12-脂氧合酶，12 S型[Alox 12]）或12/15-脂氧合酶（Alox 15）的基因的整体遗传缺失的小鼠，以比较每种基因缺失对细胞毒素链脲佐菌素的细胞功能和存活的影响。Alox 12（-/-）小鼠在暴露于链脲佐菌素后表现出比WT小鼠更大的葡萄糖耐量受损，而Alox 15（-/-）小鼠则受到保护，免受代谢障碍。这些变化伴随着Alox 12（-/-）小鼠胰岛氧化应激和Alox 15（-/-）小鼠氧化应激降低的证据，与这些小鼠胰岛中抗氧化反应酶表达的变化一致。此外，来自Alox 12（-/-）小鼠的胰岛显示Alox 15基因表达的补偿性增加，并且用12/15-脂氧合酶抑制剂ML-351治疗这些小鼠挽救了血糖异常表型。总的来说，这些结果表明，Alox 12损失激活了Alox 15的补偿性增加，使小鼠细胞对氧化应激敏感。
In type 1 diabetes, an autoimmune event increases oxidative stress in islet cells, giving rise to cellular dysfunction and apoptosis. Lipoxygenases are enzymes that catalyze the oxygenation of polyunsaturated fatty acids that can form lipid metabolites involved in several biological functions, including oxidative stress. 12-Lipoxygenase and 12/15-lipoxygenase are related but distinct enzymes that are expressed in pancreatic islets, but their relative contributions to oxidative stress in these regions are still being elucidated. In this study, we used mice with global genetic deletion of the genes encoding 12-lipoxygenase (arachidonate 12-lipoxygenase, 12S type [Alox12]) or 12/15-lipoxygenase (Alox15) to compare the influence of each gene deletion on cell function and survival in response to the cell toxin streptozotocin. Alox12(-/-) mice exhibited greater impairment in glucose tolerance following streptozotocin exposure than WT mice, whereas Alox15(-/-) mice were protected against dysglycemia. These changes were accompanied by evidence of islet oxidative stress in Alox12(-/-) mice and reduced oxidative stress in Alox15(-/-) mice, consistent with alterations in the expression of the antioxidant response enzymes in islets from these mice. Additionally, islets from Alox12(-/-) mice displayed a compensatory increase in Alox15 gene expression, and treatment of these mice with the 12/15-lipoxygenase inhibitor ML-351 rescued the dysglycemic phenotype. Collectively, these results indicate that Alox12 loss activates a compensatory increase in Alox15 that sensitizes mouse cells to oxidative stress.