Analysis of the transcriptional regulatory mechanism of nuclear receptors via posttranslational modification of the nuclear receptors and localization of the interacting factors

• Project/Area Number: 15H02896
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Eating habits
• Research Institution: Osaka University
• Principal Investigator: Keisuke Tachibana 大阪大学, 薬学研究科, 特任講師(常勤) (30432446)
• Co-Investigator(Kenkyū-buntansha): 土井 健史 大阪大学, 薬学研究科, 教授 (00211409) ; 石本 憲司 大阪大学, 薬学研究科(研究院), 助教 (00572984)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: 核内受容体 / 翻訳後修飾 / PPARα活性化剤 / 蛋白質 分解 / LPIN / SETDB1 / 分子代謝学 / 転写制御 / 活性化剤

Outline of Final Research Achievements

Both PPAR and LXR are ligand-activated transcription factors that play pivotal roles in regulating lipid homeostasis. In the present study, we developed novel PPARα ligands that act in vivo to reduce plasma triglyceride levels. We also revealed that LPIN1, having dual functions in the regulation of lipid metabolism, is degraded by the E3 ubiquitin ligase BTRC. Furthermore, we investigated the subcellular localization and enzymatic activity regulation of the histone methyltransferase SETDB1. These findings will be useful for developing the drugs to treat metabolic diseases.

Research Products

• [Journal Article] Degradation of human Lipin-1 by BTRC E3 ubiquitin ligase (2017)
  • Author(s): Ishimoto Kenji、Hayase Ayaka、Kumagai Fumiko、Kawai Megumi、Okuno Hiroko、Hino Nobumasa、Okada Yoshiaki、Kawamura Takeshi、Tanaka Toshiya、Hamakubo Takao、Sakai Juro、Kodama Tatsuhiko、Tachibana Keisuke、Doi Takefumi
  • Journal Title: Biochem Biophys Res Commun. Volume: 488 Issue: 1 Pages: 159-164
  • DOI: 10.1016/j.bbrc.2017.04.159
  • Peer Reviewed
• [Journal Article] IL-1β-induced downregulation of the multifunctional PDZ adaptor PDZK1 is attenuated by ERK inhibition, RXRα or PPARα stimulation in enterocytes. (2017)
  • Author(s): Luo M, Yeruva S, Liu Y, Chodisetti G, Riederer B, Menon MB, Tachibana K, Doi T, Seidler U
  • Journal Title: Frontiers in Physiology Volume: 8 Pages: 61-61
  • DOI: 10.3389/fphys.2017.00061
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ubiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity. (2016)
  • Author(s): Ishimoto K, Kawamata N, Uchihara Y, Okubo M, Fujimoto R, Gotoh E, Kakinouchi K, Mizohata E, Hino N, Okada Y, Mochizuki Y, Tanaka T, Hamakubo T, Sakai J, Kodama T, Inoue T, Tachibana K, Doi T
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0165766-e0165766
  • DOI: 10.1371/journal.pone.0165766
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of the subcellular localization of the human histone methyltransferase SETDB1 (2015)
  • Author(s): Tachibana K, Gotoh E, Kawamata N, Ishimoto K, Uchihara Y, Iwanari H, Sugiyama A, Kawamura T, Mochizuki Y, Tanaka T, Sakai J, Hamakubo T, Kodama T, Doi T.
  • Journal Title: Biochem Biophys Res Commun Volume: 465 Issue: 4 Pages: 725-731
  • DOI: 10.1016/j.bbrc.2015.08.065
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Development of novel non-fibrate PPARα activator for metabolic diseases (2018)
  • Author(s): Keisuke TACHIBANA, Tomohiro YUZURIHA, Ryotaro TABATA, Syohei FUKUDA, Kazuto NUNOMURA, Tadayuki KOBAYASHI, Kenji ISHIMOTO, Hiroyuki MIYACHI, Takefumi DOI
  • Organizer: 4th International Symposium of Medicinal Sciences
  • Int'l Joint Research / Invited
• [Presentation] 非アルコール性脂肪肝炎（NASH）克服を目指した新規核内受容体PPARα活性化剤の創製 (2018)
  • Author(s): 橘敬祐, 田畑遼太朗, 福田昭平, 布村一人, 土井健史
  • Organizer: 先導的学際研究機構 創薬サイエンス部門シンポジウム 「我が国が切り拓く難病治療の未来」
• [Presentation] 脂質異常症治療薬の開発を目指した新規PPARα活性化化合物の薬効と毒性の評価 (2017)
  • Author(s): 田畑遼太朗, 橘敬祐, 杠智博, 前川貴志, 福田昭平, 石本憲司, 小林直之, 田中十志也, 児玉龍彦, 宮地弘幸, 土井健史
  • Organizer: 日本薬学会 第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-27
• [Presentation] 核内受容体PPARα発現細胞株を用いたリガンドスクリーニング系の構築と新規活性化剤の探索 (2017)
  • Author(s): 橘敬祐, 田畑遼太朗, 杠智博, 福田昭平, 前川貴志, 石本憲司, 布村一人, 小林直之, 宮地弘幸, 土井健史
  • Organizer: 第21回 日本心血管内分泌代謝学会学術総会
• [Presentation] 心血管イベントの残余リスクの軽減を目指した新規核内受容体PPARα作働薬の開発 (2016)
  • Author(s): 橘敬祐, 杠智博, 田畑遼太朗, 前川貴志, 福田昭平, 石本憲司, 小林直之, 宮地弘幸, 土井健史
  • Organizer: 第1回 黒潮カンファレンス
  • Place of Presentation: 千葉
  • Year and Date: 2016-10-22
• [Presentation] 核内受容体PPARαを標的とした新規脂質異常症治療薬の開発 (2016)
  • Author(s): 田畑遼太朗, 橘敬祐, 杠智博, 前川貴志, 福田昭平, 石本憲司, 小林直之, 田中十志也, 児玉龍彦, 宮地弘幸, 土井健史
  • Organizer: 第15回 次世代を担う若手ファーマ・バイオフォーラム2016
  • Place of Presentation: 大阪
  • Year and Date: 2016-09-10
• [Presentation] 脂質異常症治療薬を目指した核内受容体PPARαの新規活性化化合物の開発 (2015)
  • Author(s): 杠智博, 橘敬祐, 前川貴志, 田畑遼太朗, 石本憲司, 小林直之, 田中十志也, 児玉龍彦, 宮地弘幸, 土井健史
  • Organizer: 第65回 日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-17
• [Presentation] 脂質代謝制御因子Lipin1と分解メカニズムの解明 (2015)
  • Author(s): 奥野紘子, 石本憲司, 熊谷文子, 早瀬絢香, 樋野展正, 橘敬祐, 川村猛, 田中十志也, 児玉龍彦, 土井健史
  • Organizer: 第16回 Pharmaco-Hematologyシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2015-06-13
• [Remarks] 大阪大学大学院薬学研究科生命情報解析学分野ホームページ
  • URL: http://www.phs.osaka-u.ac.jp/homepage/b018/
• [Remarks]
  • URL: http://www.phs.osaka-u.ac.jp/homepage/b018/index.html
• [Patent(Industrial Property Rights)] ピラゾロピリジン誘導体およびその使用 (2016)
  • Inventor(s): 土井健史, 橘敬祐, 小林直之, 杠智博, 石本憲司, 宮地弘幸
  • Industrial Property Rights Holder: 国立大学法人 大阪大学、国立大学法人 岡山大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-11-11
  • Overseas