Structural analysis of selenoprotein P as a diabetes-associated hepatokine

• Project/Area Number: 26461328
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: Kikuchi Akihiro 金沢大学, 医学系, 博士研究員 (90321752)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: セレノプロテインP / ヘパトカイン / 結晶構造解析 / ホモロジーモデリング / LDL受容体ファミリー / タンパク質相互作用解析 / 糖尿病 / セレノプロテイン / タンパク質結晶構造解析 / タンパク質構造モデル

Outline of Final Research Achievements

Selenoprotein P (SeP) is a diabetes-associated hepatokine. Structure based drug design for SeP should be one of useful techniques for screening new compounds as potential anti-diabetic drugs.
To solve the crystal structure, we have established a purification protocol of SeP from human plasma. In addition, we have established a expression and purification protocol of cysteine-substituted SeP. A homology modeling revealed that the N-terminal domain of SeP has a characteristic tertiary structure termed the thioredoxin fold, except a insertion of long loop. Such insertion may be a receptor-interacting region.
Also, we found that LRP1 is a SeP receptor in the muscle and SeP causes exercise resistance through LRP1. Biacore analysis showed that SeP specifically binds one of ligand binding domains of LRP1. Detailed analysis is now in progress.

Research Products

• [Journal Article] Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. (2017)
  • Author(s): H Misu, H Takayama, Y Saito, Y Mita, A Kikuchi, K Ishii, K Chikamoto, T Kanamori, N Tajima, F Lan, Y Takeshita, M Honda, M Tanaka, S Kato, N Matsuyama, Y Yoshioka, Iwayama K, Tokuyama K, Akazawa N, Maeda S, Takekoshi K, Matsugo S, Noguchi N, S Kaneko, T Takamura.
  • Journal Title: Nature Med Volume: 23 Issue: 4 Pages: 508-516
  • DOI: 10.1038/nm.4295
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Where does liver fat go? A possible molecular link between fatty liver and diabetes (2017)
  • Author(s): Akihiro Kikuchi, Toshinari Takamura
  • Journal Title: J. Diabetes Invest Volume: 8 Issue: 2 Pages: 152-154
  • DOI: 10.1111/jdi.12573
  • Peer Reviewed / Open Access
• [Journal Article] Rapid response of the steatosis-sensing hepatokine LECT2 during diet-induced weight cycling in mice. (2016)
  • Author(s): K Chikamoto, H Misu, H Takayama, A Kikuchi, KA Ishii, F Lan, N Takata, N Tajima-Shirasaki, Y Takeshita, H Tsugane, S Kaneko, S Matsugo, T Takamura.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 3 Pages: 1310-1316
  • DOI: 10.1016/j.bbrc.2016.08.117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Regulation of Insulin Signaling Molecules by Selective Autophagy in Mice with Proteasome Dysfunction and Starvation (2017)
  • Author(s): Akihiro Kikuchi, Hirobumi Igawa, Yumiko Tahira, Toshinari Takamura
  • Organizer: 2017 Keystone Symposia Conference
  • Place of Presentation: Keystone, Colorado, USA
  • Year and Date: 2017-01-22
  • Int'l Joint Research
• [Presentation] 糖尿病病態形成ヘパトカイン・セレノプロテインPの結晶化 (2014)
  • Author(s): 菊地 晶裕
  • Organizer: 第７回北陸合同バイオシンポジウム
  • Place of Presentation: 八尾ゆめの森（富山県富山市）
  • Year and Date: 2014-11-28 – 2014-11-29
• [Book] 実験医学増刊「「解明」から「制御」へ 肥満症のメディカルサイエンス」（1章5節「過栄養に応答した肝臓の代謝リモデリング」を分担） (2016)
  • Author(s): 菊地 晶裕、篁 俊成
  • Publisher: 羊土社