Ichikawa Atsuya, Toyama Takashi, Taguchi Hiroki, Shiina Satoru, Takashima Hayato, Takahashi Kazuaki, Ogra Yasumitsu, Mizuno Ayako, Arisawa Kotoko, Saito Yoshiro
Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
Redox Biol. 2025 Jun;83:103664. doi: 10.1016/j.redox.2025.103664. Epub 2025 May 5.
The essential trace element selenium (Se) plays a significant role in redox homeostasis, while Se is very reactive and has a potent toxicity. Understanding the molecular machinery that supports Se metabolism is important for the both physiological and pathophysiological context. Incorporated Se is translated/transformed in the liver into selenoprotein P (SeP; encoded by Selenop), an extracellular Se carrier protein that effectively transports Se to the cells via the binding to its receptor apolipoprotein E receptor 2 (ApoER2), which is taken up by cells. The present study shows that SeP is a source of Se that accumulates intracellularly and can be utilized for prolonged periods under Se-deficient conditions. In cultured cells (RD and SH-SY5Y), glutathione peroxidase (GPX) expression induced by Se supply via the SeP/ApoER2 pathway was maintained longer during Se deficiency than inorganic Se, which was promoted by ApoER2 overexpression. SeP-deficient mice showed a faster decline in brain Se levels when fed a Se-deficient diet. Preserved GPX expression induced by this SeP/ApoER2 axis contributed to oxidative stress and ferroptosis resistance, suggesting that this redundant Se metabolism contributes to prolonged Se utilization and cytoprotection.
必需微量元素硒（Se）在氧化还原稳态中发挥着重要作用，然而硒具有高反应活性且毒性很强。了解支持硒代谢的分子机制对于生理和病理生理背景都很重要。摄入的硒在肝脏中被转化为硒蛋白P（SeP；由Selenop编码），这是一种细胞外硒载体蛋白，它通过与细胞表面受体载脂蛋白E受体2（ApoER2）结合，有效地将硒转运到细胞中，随后细胞摄取该复合物。本研究表明，SeP是细胞内积累的硒的来源，并且在缺硒条件下可以长时间被利用。在培养细胞（RD和SH-SY5Y）中，通过SeP/ApoER2途径供应硒所诱导的谷胱甘肽过氧化物酶（GPX）表达，在缺硒期间比无机硒维持的时间更长，ApoER2的过表达促进了这种作用。缺硒饮食喂养的SeP缺陷小鼠脑内硒水平下降更快。由该SeP/ApoER2轴诱导的GPX表达得以维持，有助于抵抗氧化应激和铁死亡，这表明这种冗余的硒代谢有助于延长硒的利用时间并提供细胞保护。
