Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Cell Metab. 2010 Nov 3;12(5):483-95. doi: 10.1016/j.cmet.2010.09.015.
The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes.
肝脏可以通过产生分泌蛋白（称为肝分泌因子）来调节外周组织对胰岛素的敏感性/抵抗性，从而调节葡萄糖稳态。在这里，我们证明了一种肝脏来源的分泌蛋白硒蛋白 P（SeP）会导致胰岛素抵抗。我们使用基因表达序列分析（SAGE）和 DNA 芯片方法发现，人类肝脏 SeP mRNA 水平与胰岛素抵抗相关。纯化的 SeP 可损害肝细胞和肌细胞中的胰岛素信号转导并扰乱葡萄糖代谢。相反，SeP 的基因缺失和 RNA 干扰介导的敲低均可改善小鼠的全身胰岛素敏感性和葡萄糖耐量。SeP 的代谢作用至少部分是通过腺苷单磷酸激活蛋白激酶（AMPK）失活介导的。总之，这些结果表明 SeP 在调节葡萄糖代谢和胰岛素敏感性方面发挥作用，并提示 SeP 可能是 2 型糖尿病的治疗靶标。
