Development of NASH therapeutics by regulating energy expenditure and inflammation through the lipid sensor PPAR

• Project/Area Number: 18H03190
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Osaka University
• Principal Investigator: Keisuke TACHIBANA 大阪大学, 薬学研究科, 講師 (30432446)
• Co-Investigator(Kenkyū-buntansha): 土井 健史 大阪大学, 薬学研究科, 特任教授 (00211409) ; 吉田 卓也 大阪大学, 薬学研究科, 准教授 (00294116) ; 石本 憲司 大阪大学, 薬学研究科, 特任講師(常勤) (00572984) ; 樋野 展正 大阪大学, 薬学研究科, 講師 (90469916)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 核内受容体 / NASH / 分子代謝学 / PPAR / 立体構造解析 / LPIN / PGAM5 / リガンド / 分子病態学

Outline of Final Research Achievements

The nuclear receptor PPAR and its regulators upregulate lipid metabolism and are promising target molecules for the prevention and treatment of nonalcoholic steatohepatitis (NASH). We established a screening system for PPAR activators and obtained new PPAR ligands. Based on co-crystal structure analysis of this compound and PPAR, we developed more active compounds. These compounds exhibited inhibitory effects on liver fibrosis in NASH model mice. In addition, we revealed that LPIN, which regulates PPAR in the nucleus, is dephosphorylated by PGAM5 and translocated from the cytoplasm to the nucleus. These findings will be useful for for the development of new therapeutics for NASH.

Academic Significance and Societal Importance of the Research Achievements

近年の食生活や運動不足によるエネルギー過剰の状態は、体内に余剰の脂肪蓄積を促し肥満となる。それと共に脂肪肝から肝線維化を経て肝硬変、肝癌へと至る非アルコール性脂肪肝炎(NASH)に罹患する患者数も急増している。本研究は、脂質センサー分子であるPPARの制御機構を解明すると共に、新たな活性化剤の開発に関する研究であり、今回得られた知見を基に新たなNASH治療法を提案できることから、非常に意義深いものである。

Research Products

• [Journal Article] Exploring Compounds to be used as Cosmetic Agents that Activate Peroxisome Proliferator‐Activated Receptor Alpha (2022)
  • Author(s): Tachibana Keisuke、Fukuda Syohei、Fukushima Jun、Ishimoto Kenji、Sakata Masahiro、Nishimori Yasutomo、Doi Takefumi
  • Journal Title: International Journal of Cosmetic Science Volume: - Issue: 2 Pages: 189-200
  • DOI: 10.1111/ics.12767
  • Peer Reviewed / Open Access
• [Journal Article] Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives. (2020)
  • Author(s): Yoshida T, Oki H, Doi M, Fukuda S, Yuzuriha T, Tabata R, Ishimoto K, Kawahara K, Ohkubo T, Miyachi H, Doi T, Tachibana K.
  • Journal Title: Scientific Reports Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Ligand Screening Tool Using Full-Length Human Peroxisome Proliferator-Activated Receptor-Expressing Cell Lines to Ameliorate Metabolic Syndrome (2019)
  • Author(s): Tachibana Keisuke、Ishimoto Kenji、Takahashi Rika、Kadono Hirokazu、Awaji Takuya、Yuzuriha Tomohiro、Tanaka Toshiya、Hamakubo Takao、Sakai Juro、Kodama Tatsuhiko、Aoki Shunji、Doi Takefumi
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 67 Issue: 3 Pages: 199-202
  • DOI: 10.1248/cpb.c18-00627
  • NAID: 130007605823
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2019-03-01
  • Peer Reviewed
• [Journal Article] Structural development of 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid derivatives as human peroxisome proliferator-activated receptor alpha (PPARα)-selective agonists (2019)
  • Author(s): Miyachi Hiroyuki、Yuzuriha Tomohiro、Tabata Ryotaro、Fukuda Syohei、Nunomura Kazuto、Lin Bangzhong、Kobayashi Tadayuki、Ishimoto Kenji、Doi Takefumi、Tachibana Keisuke
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 29 Issue: 16 Pages: 2124-2128
  • DOI: 10.1016/j.bmcl.2019.06.062
  • Peer Reviewed
• [Journal Article] Lipin-1 is a novel substrate of protein phosphatase PGAM5 (2019)
  • Author(s): Okuno Hiroko、Okuzono Haruna、Hayase Ayaka、Kumagai Fumiko、Tanii Shohei、Hino Nobumasa、Okada Yoshiaki、Tachibana Keisuke、Doi Takefumi、Ishimoto Kenji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 509 Issue: 4 Pages: 886-891
  • DOI: 10.1016/j.bbrc.2019.01.031
  • Peer Reviewed
• [Journal Article] Discovery of peroxisome proliferator?activated receptor α (PPARα) activators with a ligand-screening system using a human PPARα-expressing cell line (2018)
  • Author(s): Tachibana Keisuke、Yuzuriha Tomohiro、Tabata Ryotaro、Fukuda Syohei、Maegawa Takashi、Takahashi Rika、Tanimoto Keiichi、Tsujino Hirofumi、Nunomura Kazuto、Lin Bangzhong、Matsuura Yoshiharu、Tanaka Toshiya、Hamakubo Takao、Sakai Juro、Kodama Tatsuhiko、Kobayashi Tadayuki、Ishimoto Kenji、Miyachi Hiroyuki、Doi Takefumi
  • Journal Title: Journal of Biological Chemistry Volume: 293 Issue: 26 Pages: 10333-10343
  • DOI: 10.1074/jbc.ra118.002077
  • Peer Reviewed
• [Presentation] 新規PPARα作動薬の創出とその構造展開 (2020)
  • Author(s): 宮地 弘幸、布村 一人、林 邦忠、土井 健史、橘 敬祐
  • Organizer: 日本薬学会 第140年会
• [Presentation] 非アルコール性脂肪肝炎（NASH）克服を目指した核内受容体PPARαの新規活性化剤の創製 (2020)
  • Author(s): 橘敬祐, 土井健史
  • Organizer: 第93回日本薬理学会年会
  • Invited
• [Presentation] 皮膚機能を改善する核内受容体PPARα活性化成分の探索 (2019)
  • Author(s): 福田昭平、橘敬祐、福島純、阪田昌弘、西森康友、土井健史
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acids as human peroxisome proliferator-activated receptor (PPAR) alpha-selective agonists (2019)
  • Author(s): Hiroyuki Miyachi, Kazuto Nunomura, Bangzhong Lin,Takefumi Doi, Keisuke Tachibana
  • Organizer: 第37回メディシナルケミストリーシンポジウム
• [Presentation] 生活習慣病治療薬開発を目指した新規PPAR alpha作動薬としてのピラゾロピリジン誘導体の開発 (2019)
  • Author(s): 橘敬祐, 福田昭平, 杠智博, 田畑遼太朗, 布村一人, 林邦忠, 小林直之, 石本憲司, 宮地弘幸, 土井健史
  • Organizer: 第92回日本生化学会大会
• [Presentation] Development Of Novel Non-fibrate Peroxisome Proliferator-activated Receptor Ligand For Treating Nonalcoholic Steatohepatitis (2018)
  • Author(s): Keisuke TACHIBANA, Tomohiro YUZURIHA, Ryotaro TABATA, Syohei FUKUDA, Kazuto NUNOMURA, Bangzhong LIN, Tadayuki KOBAYASHI, Masuo KONDOH, Kenji ISHIMOTO, Hiroyuki MIYACHI, Takefumi DOI
  • Organizer: CRS Annual Meeting
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] ＰＰＡＲα活性化剤 (2021)
  • Inventor(s): 土井健史、橘敬祐、福田昭平、福島純、阪田昌弘
  • Industrial Property Rights Holder: 土井健史、橘敬祐、福田昭平、福島純、阪田昌弘
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-162499
  • Filing Date: 2021
• [Patent(Industrial Property Rights)] ＰＰＡＲα転写活性化剤およびその医薬用途 (2021)
  • Inventor(s): 土井健史,橘敬祐,赤井周司,吉田卓也,森江俊哉,辻川和丈ら
  • Industrial Property Rights Holder: 土井健史,橘敬祐,赤井周司,吉田卓也,森江俊哉,辻川和丈ら
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-095378
  • Filing Date: 2021