TY - JOUR
T1 - A liver-derived secretory protein, selenoprotein P, causes insulin resistance
AU - Misu, Hirofumi
AU - Takamura, Toshinari
AU - Takayama, Hiroaki
AU - Hayashi, Hiroto
AU - Matsuzawa-Nagata, Naoto
AU - Kurita, Seiichiro
AU - Ishikura, Kazuhide
AU - Ando, Hitoshi
AU - Takeshita, Yumie
AU - Ota, Tsuguhito
AU - Sakurai, Masaru
AU - Yamashita, Tatsuya
AU - Mizukoshi, Eishiro
AU - Yamashita, Taro
AU - Honda, Masao
AU - Miyamoto, Ken Ichi
AU - Kubota, Tetsuya
AU - Kubota, Naoto
AU - Kadowaki, Takashi
AU - Kim, Han Jong
AU - Lee, In Kyu
AU - Minokoshi, Yasuhiko
AU - Saito, Yoshiro
AU - Takahashi, Kazuhiko
AU - Yamada, Yoshihiro
AU - Takakura, Nobuyuki
AU - Kaneko, Shuichi
N1 - Funding Information:
We thank Kuniaki Arai of Kanazawa University for liver biopsies and Isao Usui, Hajime Ishihara, and Toshiyasu Sasaoka of Toyama University for supplying their technical expertise on Western blot analyses of phosphoproteins. We thank Yuriko Furuta and Yoko Hashimoto for technical assistance. We thank Fabienne Foufelle of Université Pierre et Marie Curie for providing adenovirus vector encoding DN-AMPK. We are indebted to Kristina E. Hill and Raymond F. Burk of Vanderbilt University School of Medicine for the Sepp1 knockout mice. This work was supported by Takeda Science Foundation and Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We also thank Cathie Chung for editing the manuscript.
PY - 2010/11/3
Y1 - 2010/11/3
N2 - 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.
AB - 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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U2 - 10.1016/j.cmet.2010.09.015
DO - 10.1016/j.cmet.2010.09.015
M3 - Article
C2 - 21035759
AN - SCOPUS:78049428301
SN - 1550-4131
VL - 12
SP - 483
EP - 495
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -
