Nuclear in situ metabolisms and nuclear receptors.

• Project/Area Number: 20K20592
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Tohoku University
• Principal Investigator: Ogura Toshihiko 東北大学, 加齢医学研究所, 教授 (60273851)
• Project Period (FY): 2020-07-30 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000); Fiscal Year 2023: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2021: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2020: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 核内受容体 / リガンド / 核内脂質 / 核内脂質代謝系 / エネルギー代謝 / 質量分析 / Spermidine / 核内代謝 / 脂質代謝

Outline of Research at the Start

本研究では、以下の3つを行う。
1）核内脂質の分析　本研究で詳細な質量分析を行い、核内核脂質成分を同定する。
2）細胞の変化による脂質成分変動の把握　C2C12細胞は、力学刺激によって骨格筋細胞や脂肪細胞にも分化する。未分化C2C12、分化Type IIa/IIb骨格筋細胞、脂肪細胞について、細胞質／核脂質の質量分析を行う。
3）生理的意義の解明　骨格筋のエネルギー代謝、脂肪細胞分化に関与する核内受容体について、細胞質／核内脂質がagonist活性を持つかを検証する。同定された脂質は、マウス個体にに応用する。また、廃用性萎縮骨格筋の核脂質の組成差、若いマウスと老齢マウスの組成差なども解析する。

Outline of Final Research Achievements

In this research project, we found and analyzed several factors that rapidly shuttle from cytoplasm into nucleus in response to mechanical stimuli. Interestingly, some of these factors are lipid metabolizing enzymes, suggesting that even in the nucleus, these enzymes constitute unique metabolic systems, by which ligands of nuclear receptors are synthesized in situ to regulate cellular energy metabolism. To uncover the nuclear lipid metabolism, we have identified many nuclear enzymes extensively. In addition, we analyzed nuclear lipids by MASS spectrometry in a semi-comprehensive way and made detailed lists of the cytoplasmic and nuclear lipids, which provide important information and insights on the nuclear lipids and their unique metabolic pathways. Our research opened a new direction and made a novel concept on the nuclear lipids, which has never been described.

Academic Significance and Societal Importance of the Research Achievements

核内受容体のリガンドは，ホルモンとして異なる組織で生成され，血流で運ばれて標的組織の受容体を活性化すると考えられてきた。しかし，基本的に水溶性の低い脂質様リガンドが，このようなステップで動いているのか，多くの疑問があった。今回の研究成果から，核内にも脂質代謝系が存在し，核内受容体リガンドとなる脂質を生成できること，核と細胞質の脂質に大きな違いがあることがわかり，肥満，糖尿病の発症にも関与する核内リガンドの見解に新しい局面を開いた。核内にユニークな脂質代謝系があること自体，大きな発見であり，この学術的意義はきわめて大きく，内在性核内受容体リガンドの研究に大きな一石を投じることとなった。

Research Products

• [Journal Article] Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. (2022)
  • Author(s): Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, Sonomura K, Maharani A, Nakajima Y, Wu Y, Nomura Y, Menzies R, Tajima M, Kitaoka K, Haku Y, Delghandi S, Yurimoto K, Matsuda F, Iwata S, Ogura T, Fagarasan S, Honjo T.
  • Journal Title: Science Volume: 378 Issue: 6618
  • DOI: 10.1126/science.abj3510
  • Peer Reviewed / Open Access
• [Journal Article] Structural insights into vesicle amine transport-1 (VAT-1) as a member of the NADPH-dependent quinone oxidoreductase family (2021)
  • Author(s): Kim Sun-Yong、Mori Tomoyuki、Chek Min Fey、Furuya Shunji、Matsumoto Ken、Yajima Taisei、Ogura Toshihiko、Hakoshima Toshio
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-81409-y
  • Peer Reviewed
• [Journal Article] Findings from recent studies by the Japan Aerospace Exploration Agency examining musculoskeletal atrophy in space and on Earth (2020)
  • Author(s): Atsushi Higashitani et al
  • Journal Title: npj microgravity Volume: 1
  • Peer Reviewed