Elucidation of anti-obese mechanism via the retinoic acid receptor signal controlled by SMRT

• Project/Area Number: 18K08486
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Dokkyo Medical University
• Principal Investigator: Shimizu Hiroaki 獨協医科大学, 医学部, 助教 (60594398)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 核内受容体 / 転写抑制補助因子 / 肥満 / レチノイド / 内臓脂肪 / SMRT / ビタミンA / レチノイン酸 / 転写抑制因子 / Corepressor / 脂質代謝

Outline of Final Research Achievements

We recently reported that the nuclear corepressor; SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action (Shimizu H, et al. PLoS One 2019).

In addition, by the proteomics analysis using LC-MS/MS, we found that a variety of catabolic enzymes for retinoic acids were up-regulated in the liver of global deletion of SMRT KO mice. This suggests the possibility that the degradation of retinoic acids aggravates in the mouse liver. These are the remarkable findings which clarify the mechanism that the depletion of retinoic acid induces fat accumulation in organ.

Academic Significance and Societal Importance of the Research Achievements

飽食が社会問題となる一方、栄養素のレチノイン酸（ビタミンA）の不足はかえって肥満を誘引するという報告が増えているが、詳細機序は不明である。
SMRTはレチノイン酸受容体に結合し遺伝子転写を抑制する分子である。筆者は、本研究でSMRT欠失マウスは内臓肥満（脂肪肝）をきたすことを報告した。更に同マウスの肝臓を質量分析器で詳しく解析し、肝臓内でレチノイド代謝酵素群が高発現することを確認した。即ちSMRTが代謝酵素群の発現を制御し、肝臓でのレチノイド消費を防ぐことにより、全身の内臓脂肪の蓄積を抑制する機序が考えられた。本結果はSMRTを標的とした新たな肥満治療の開発につながる可能性を示唆する。

Research Products

• [Int'l Joint Research] Weill Cornell Medicine/University of Chicago(米国)
• [Journal Article] Nuclear corepressor SMRT is a strong regulator of body weight independently of its ability to regulate thyroid hormone action (2019)
  • Author(s): Hiroaki Shimizu, Yu Lu, Kristen R. Vella, Federico Damilano, Inna Astapova, Izuki Amano, Megan Ritter, Molly R. Gallop, Anthony N. Rosenzweig, Ronald N. Cohen, Anthony N. Hollenberg
  • Journal Title: PLOS ONE Volume: Aug 12;14(8):e0220717 Issue: 8 Pages: 1-18
  • DOI: 10.1371/journal.pone.0220717
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Nuclear Corepressor; SMRT Acts as an Important Regulator for Both Beta-Oxidation and the Maturation of Myogenesis in Mouse C2C12 Cell (2020)
  • Author(s): Hiroaki Shimizu, Yasuhiro Horibata, Chieko Aoyama, Izuki Amano, Megan Ritter, Hiromi Ando, Hiroyuki Sugimoto, Anthony Neil Hollenberg
  • Organizer: Endocrine Society 2020
  • Int'l Joint Research
• [Presentation] Nuclear corepressor; SMRT acts as an important regulator for both beta-oxidation and the maturation of myogenesis in mouse C2C12 cell (2020)
  • Author(s): Hiroaki Shimizu, Yasuhiro Horibata, Chieko Aoyama, Izuki Amano, Megan Ritter, Hiromi Ando, Hiroyuki Sugimoto, Ronald N Cohen, Anthony N Hollenberg
  • Organizer: The 102nd Endocrine Society Annual Meeting & Expo; ENDO 2020
  • Int'l Joint Research