A Liver-Derived Secretory Protein, Selenoprotein P, Causes Insulin Resistance

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. Usi...

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Bibliographic Details
Published in:Cell metabolism 2010-11, Vol.12 (5), p.483-495
Main 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
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - metabolism
Animals
Cell Line
Diabetes Mellitus, Type 2 - metabolism
Female
Gene Deletion
Gene Expression Regulation
Glucose - metabolism
Hepatocytes - metabolism
Humans
Insulin Resistance
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Palmitic Acid - metabolism
Phosphorylation
Rats
RNA Interference
RNA, Messenger - genetics
Selenoprotein P - genetics
Selenoprotein P - metabolism
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Summary: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. [Display omitted] ► SeP emerged from human liver screen for hepatokines involved in insulin resistance ► Glucose or palmitate increases SeP mRNA, whereas insulin decreases it in hepatocytes ► SeP induces insulin resistance in liver and muscle, resulting in hyperglycemia ► SeP dephosphorylates AMPK in hepatocytes in an AMP/ATP ratio-independent manner
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2010.09.015