Role of selenoprotein P expression in the function of pancreatic β cells: Prevention of ferroptosis-like cell death and stress-induced nascent granule degradation
Role of selenoprotein P expression in the function of pancreatic β cells: Prevention of ferroptosis-like cell death and stress-induced nascent granule degradation
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DOI：
10.1016/j.freeradbiomed.2022.03.009
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发表时间：
2022-03-22
影响因子：
7.4
通讯作者：
Toyama, Takashi
中科院分区：
文献类型：
--
作者：
Kitabayashi, Nanako;Nakao, Shohei;Toyama, Takashi
硒蛋白P（Selenoprotein P，简称SELENP）是人体血浆中主要的含硒蛋白，主要在肝脏中合成。SELENOP将硒转运到细胞中，而在外周组织中合成的SELENOP以旁分泌/自分泌方式掺入，以维持细胞硒蛋白的水平，称为SELENOP循环。已知负责胰岛素合成和分泌的胰腺β细胞表达SELENOP。在这里，使用MIN 6细胞作为胰腺β细胞和Selenop小干扰（si）RNA的小鼠模型，我们发现Selenop基因敲低（KD）导致细胞活力、细胞胰岛素原/胰岛素水平、胰岛素分泌和几种细胞硒蛋白的水平降低，包括谷胱甘肽过氧化物酶4（Gpx 4）和硒蛋白K（Selenok）。这些功能障碍诱导Selenop siRNA的恢复通过添加硒。由Gpx 4调节的铁中毒样细胞死亡参与Selenop KD降低细胞活力，而由Selenok调节的应激诱导的新生颗粒降解（SINGD）负责胰岛素原的减少。在Selenop敲除小鼠的胰腺β细胞中也观察到SINGD。这些发现表明，通过维持细胞硒蛋白（如GPX 4和SELENOK）的水平，SELENOP表达对胰腺β细胞功能具有重要作用。
Selenoprotein P (SELENOP) is a major selenium (Se)-containing protein (selenoprotein) in human plasma that is mainly synthesized in the liver. SELENOP transports Se to the cells, while SELENOP synthesized in peripheral tissues is incorporated in a paracrine/autocrine manner to maintain the levels of cellular selenoproteins, called the SELENOP cycle. Pancreatic beta cells, responsible for the synthesis and secretion of insulin, are known to express SELENOP. Here, using MIN6 cells as a mouse model for pancreatic beta cells and Selenop small interfering (si)RNA, we found that Selenop gene knockdown (KD) resulted in decreased cell viability, cellular pro/insulin levels, insulin secretion, and levels of several cellular selenoproteins, including glutathione peroxidase 4 (Gpx4) and selenoprotein K (Selenok). These dysfunctions induced by Selenop siRNA were recovered by the addition of Se. Ferroptosis-like cell death, regulated by Gpx4, was involved in the decrease of cell viability by Selenop KD, while stress-induced nascent granule degradation (SINGD), regulated by Selenok, was responsible for the decrease in proinsulin. SINGD was also observed in the pancreatic beta cells of Selenop knockout mice. These findings indicate a significant role of SELENOP expression for the function of pancreatic beta cells by maintaining the levels of cellular selenoproteins such as GPX4 and SELENOK.