Analysis of regulation of lipid metabolism by vitamin D metabolite

• Project/Area Number: 26350972
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical biology
• Research Institution: Hokkaido University (2015-2016); Kyoto University (2014)
• Principal Investigator: WATANABE Mizuki 北海道大学, 薬学研究院, 講師 (20507173)
• 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: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ビタミンD / 脂質代謝 / SREBP / SCAP

Outline of Final Research Achievements

This study revealed that an endogenous vitamin D metabolite suppresses the lipid biosynthesis. Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation. Unlike sterols and other SREBP inhibitors, 25OHD impairs SREBP activation by inducing proteolytic processing and ubiquitin-mediated degradation of SCAP, thereby decreasing SREBP levels independently of the vitamin D receptor. Vitamin D supplementation has been proposed to reduce the risk of metabolic diseases, but the mechanisms are unknown. The present results suggest a previously unrecognized molecular mechanism of vitamin D-mediated lipid control that might be useful in the treatment of metabolic diseases.

Research Products

• [Journal Article] Vitamin D metabolite, 25-Hydroxyvitamin D, regulates lipid metabolism by inducing degradation of SREBP/SCAP. (2017)
  • Author(s): Asano, L., Watanabe, M., Ryoden, Y., Usuda, K., Yamaguchi, T., Khambu, B., Takashima, M., Sato, S., Sakai, J., Nagasawa, K., Uesugi, M.
  • Journal Title: Cell Chem Biol. Volume: 24 Issue: 2 Pages: 207-217
  • DOI: 10.1016/j.chembiol.2016.12.017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis of mevalonate- and fluorinated mevalonate prodrugs and their in vitro human plasma stability (2015)
  • Author(s): Kang, S.; Watanabe, M.; Jacobs, J.C.; Yamaguchi, M.; Dahesh, S.; Nizet, V.; Leyh, T. S.; Silverman, R.B.
  • Journal Title: Eur. J. Med. Chem. Volume: 90 Pages: 448-461
  • DOI: 10.1016/j.ejmech.2014.11.040
  • Peer Reviewed
• [Journal Article] Live-cell Imaging of Endogenous mRNAs with a Small Molecule (2015)
  • Author(s): Sato, S.*, Watanabe, M., Katsuda, Y., Murata, A., Wang, D. O., Uesugi M.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 54 Issue: 6 Pages: 1855-1858
  • DOI: 10.1002/anie.201410339
  • NAID: 120005619801
  • Peer Reviewed
• [Journal Article] Synthetic molecules that protect cells from anoikis and their use in cell transplantation (2014)
  • Author(s): Frisco-C., H.L.; Watanabe, M.; Okumura, N.; Kusamori, K.; Takemoto, N.; Takaya, J.; Sato, S.; Yamazoe, S.; Takakura, Y.; Kinoshita, S.; Nishikawa, M.; Koizumi, N.; Uesugi, M.
  • Journal Title: Angew. Chem., Int. Ed. Volume: 53 Issue: 42 Pages: 11208-11213
  • DOI: 10.1002/ange.201405829
  • Peer Reviewed
• [Presentation] 25‐ヒドロキシビタミンDによるSREBP-SCAPの分解メカニズムの解明 (2017)
  • Author(s): 浅野理沙、渡邉瑞貴、領田優太、長澤和夫、上杉志成
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 東北大学（宮城県仙台市）
  • Year and Date: 2017-03-24
• [Presentation] 25‐ヒドロキシビタミンDによるSCAP/SREBPの分解メカニズムの解明 (2016)
  • Author(s): 浅野理沙、渡邉瑞貴、領田優太、長澤和夫、上杉志成
  • Organizer: 第58回天然有機化合物討論会
  • Place of Presentation: 東北大学（宮城県仙台市）
  • Year and Date: 2016-09-15
• [Presentation] 細胞内Ca2+動員情報伝達系の機構解明を目指した環状ADP-リボース誘導体の設計と合成 (2016)
  • Author(s): 渡邉瑞貴、佐藤隆俊、加藤広太郎、福田隼、村山尚、東田陽博、周東智
  • Organizer: 日本ケミカルバイオロジー学会第11回年会
  • Place of Presentation: 京都テルサ（京都府京都市）
  • Year and Date: 2016-06-15
• [Presentation] ケミカルバイオロジーによるビタミンD誘導体の新機能研究 (2016)
  • Author(s): 渡邉瑞貴
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-26
  • Invited
• [Presentation] 内因性小分子による脂質生合成抑制機構の解明 (2015)
  • Author(s): 渡邉瑞貴、浅野理沙、領田優太、薄田晃佑、 飯田圭介、佐藤慎一、長澤和夫、上杉志成
  • Organizer: 日本ケミカルバイオロジー学会 第10回年会
  • Place of Presentation: 東北大学百周年記念会館 川内萩ホール（宮城県仙台市）
  • Year and Date: 2015-06-11
• [Presentation] ビタミン D 誘導体のケミカルバイオロジー研究 (2015)
  • Author(s): 渡邉瑞貴
  • Organizer: 第1回 有機化学を基盤とした創薬研究シンポジウム
  • Place of Presentation: 定山渓ホテル（北海道札幌市）
  • Year and Date: 2015-05-23
  • Invited
• [Presentation] 内因性低分子化合物による新規脂質代謝制御メカニズムの解明 (2015)
  • Author(s): 浅野理沙
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 脂質生合成を抑制する内因性小分子化合物 (2014)
  • Author(s): 渡邉瑞貴
  • Organizer: 第56回天然有機化合物討論会
  • Place of Presentation: 高知
  • Year and Date: 2014-10-15 – 2014-10-17
• [Presentation] 内在性mRNA細胞内動態の新規イメージング法の開発 (2014)
  • Author(s): 佐藤慎一
  • Organizer: 第８回バイオ関連化学シンポジウム
  • Place of Presentation: 岡山
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] アノイキス抑制合成分子とその細胞移植への利用 (2014)
  • Author(s): Frisco-C., Heidie L.
  • Organizer: 日本ケミカルバイオロジー学会第９回年会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-11 – 2014-06-13
• [Remarks] 京都大学ホームページ 研究成果
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2016/170127_1.html
• [Remarks] 日本の研究.com プレスリリース
  • URL: https://research-er.jp/articles/view/54774
• [Patent(Industrial Property Rights)] Compositions and methods for the treatment of metabolic disorders (2016)
  • Inventor(s): 上杉志成、渡邉瑞貴、他
  • Industrial Property Rights Holder: 上杉志成、渡邉瑞貴、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-05-24
  • Acquisition Date: 2016-09-08
  • Overseas
• [Patent(Industrial Property Rights)] Vitamin D3 derivatives and pharmaceutical use thereof (2014)
  • Inventor(s): 渡邉瑞貴、浅野理沙、長澤和夫、上杉志成
  • Industrial Property Rights Holder: 渡邉瑞貴、浅野理沙、長澤和夫、上杉志成
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-12-24
  • Overseas
• [Patent(Industrial Property Rights)] Compositions and methods for the treatment of metabolic disorders (2014)
  • Inventor(s): 上杉志成、渡邉瑞貴、他
  • Industrial Property Rights Holder: 上杉志成、渡邉瑞貴、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-06-20
  • Overseas
• [Patent(Industrial Property Rights)] Preparation of fatostatin A and derivatives and compositions thereof for the treatment of obesity (2014)
  • Inventor(s): 上杉志成、渡邉瑞貴、他
  • Industrial Property Rights Holder: 上杉志成、渡邉瑞貴、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-05-05
  • Overseas