A liver-derived secretory protein, selenoprotein P, causes insulin resistance |
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Authors: | Misu Hirofumi Takamura Toshinari Takayama Hiroaki Hayashi Hiroto Matsuzawa-Nagata Naoto Kurita Seiichiro Ishikura Kazuhide Ando Hitoshi Takeshita Yumie Ota Tsuguhito Sakurai Masaru Yamashita Tatsuya Mizukoshi Eishiro Yamashita Taro Honda Masao Miyamoto Ken-ichi Kubota Tetsuya Kubota Naoto Kadowaki Takashi Kim Han-Jong Lee In-kyu Minokoshi Yasuhiko Saito Yoshiro Takahashi Kazuhiko Yamada Yoshihiro Takakura Nobuyuki Kaneko Shuichi |
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Institution: | Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan. |
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Abstract: | 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. |
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