Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
Commun Biol. 2023 Oct 19;6(1):1060. doi: 10.1038/s42003-023-05449-y.
Selenoprotein P (SeP) is a major selenoprotein in serum predominantly produced in the liver. Excess SeP impairs insulin secretion from the pancreas and insulin sensitivity in skeletal muscle, thus inhibition of SeP could be a therapeutic strategy for type 2 diabetes. In this study, we examine the effect of sulforaphane (SFN), a phytochemical of broccoli sprouts and an Nrf2 activator, on SeP expression in vitro and in vivo. Treatment of HepG2 cells with SFN decreases inter- and intra-cellular SeP levels. SFN enhances lysosomal acidification and expression of V-ATPase, and inhibition of this process cancels the decrease of SeP by SFN. SFN activates Nrf2 in the cells, while Nrf2 siRNA does not affect the decrease of SeP by SFN or lysosomal acidification. These results indicate that SFN decreases SeP by enhancing lysosomal degradation, independent of Nrf2. Injection of SFN to mice results in induction of cathepsin and a decrease of SeP in serum. The findings from this study are expected to contribute to developing SeP inhibitors in the future, thereby contributing to treating and preventing diseases related to increased SeP.
硒蛋白 P（SeP）是血清中的一种主要硒蛋白，主要由肝脏产生。过量的 SeP 会损害胰腺的胰岛素分泌和骨骼肌的胰岛素敏感性，因此抑制 SeP 可能是治疗 2 型糖尿病的一种策略。在这项研究中，我们研究了西兰花芽中植物化学物质和 Nrf2 激活剂——萝卜硫素（SFN）对体外和体内 SeP 表达的影响。SFN 处理 HepG2 细胞可降低细胞内外 SeP 水平。SFN 增强溶酶体酸化和 V-ATPase 的表达，而抑制这一过程会消除 SFN 对 SeP 的降低作用。SFN 在细胞中激活 Nrf2，而 Nrf2 siRNA 不影响 SFN 或溶酶体酸化对 SeP 的降低作用。这些结果表明，SFN 通过增强溶酶体降解来降低 SeP，这与 Nrf2 无关。SFN 注射到小鼠体内会诱导组织蛋白酶并降低血清中的 SeP。这项研究的结果有望为未来开发 SeP 抑制剂做出贡献，从而有助于治疗和预防与 SeP 增加相关的疾病。
