Roles of Pin1 and PAR 14 on the metabolic regulations

• Project/Area Number: 17H04200
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Hiroshima University
• Principal Investigator: Asano Tomoichiro 広島大学, 医系科学研究科(医), 教授 (70242063)
• Co-Investigator(Kenkyū-buntansha): 中津 祐介 広島大学, 医系科学研究科(医), 講師 (20452584) ; 山本屋 武 広島大学, 医系科学研究科(医), 助教 (50760013)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: Pin1 / 糖尿病 / 肥満 / 代謝 / メタボリックシンドローム / 糖代謝 / 脂質代謝 / 熱産生 / Ｐｉｎ１ / 基礎代謝 / ＰＲＤＭ１６ / 腎症 / 糖・脂質代謝 / 網膜症 / 脂肪細胞 / プロリン異性化酵素

Outline of Final Research Achievements

Prolyl isomerases are divided into three groups, the FKBP family, Cyclophilin and the Parvulin family (Pin1 and Par14). Among these isomerases, Pin1 is a unique prolyl isomerase binding to the motif including pSer/pThr-Pro that is phosphorylated by kinases. Once bound, Pin1 modulates the enzymatic activity, protein stability or subcellular localization of target proteins by changing the cis- and trans- formations of proline.　 Interestingly, while Pin1 expression is markedly increased by high-fat diet feeding, Pin1 KO mice are resistant to diet-induced obesity, non-alcoholic steatohepatitis and diabetic vascular dysfunction. These phenomena result from the binding of Pin1 to several key factors regulating metabolic functions, which include insulin receptor substrate-1, AMPK, Crtc2 and NF-kappaB p65.

Academic Significance and Societal Importance of the Research Achievements

我々の一連の研究成果より、肥満や脂肪感を含めたメタボリックシンドロームの発症にPin1が必須の役割を果たしていることが明らかとなった。実際、Pin1の遺伝子欠損マウスは、これらの疾患の発症に抵抗性である。従って、Pin1の活性を抑制する薬剤が治療方法になりうることが示された。我々は、その目的を目指しており、多数のPin1阻害化合物を開発しており、社会的意義のある成果である。

Research Products

• [Journal Article] Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells. (2020)
  • Author(s): Nakatsu, Y., Yamamotoya, T., Ueda, K., Ono, H., Inoue, MK., Matsunaga, Y., Kushiyama, A., Sakoda, H., Fujishiro, M., Matsubara, A., and Asano, T.
  • Journal Title: Cancer Lett. Volume: 470 Pages: 106-114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-inflammatory effects of miRNA-146a induced in adipose and periodontal tissues. (2020)
  • Author(s): Sanada, T., Sano, T., Sotomaru, Y., Alshargabi, R., Yamawaki, Y., Yamashita, A., Matsunaga, H., Iwashita, M., Shinjo, T., Kanematsu, T., Asano, T., and Nishimura, F.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 22 Pages: 100757-100757
  • Peer Reviewed / Open Access
• [Journal Article] Possible Involvement of Normalized Pin1 Expression Level and AMPK Activation in the Molecular Mechanisms Underlying Renal Protective Effects of SGLT2 Inhibitors in Mice. (2019)
  • Author(s): Inoue, MK., Matsunaga, Y., Nakatsu, Y., Yamamotoya, T., Ueda, K., Kushiyama, A., Sakoda, H., Fujishiro, M., Ono, H., Iwashita, M., Sano, T., Nishimura, F., Morii, K., Sasaki, K., Masaki, T., and Asano, T
  • Journal Title: Diabetol. Metab. Syndr. Volume: 11 Pages: 57-57
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu, Y., Matsunaga, Y., Yamamotoya, T., Sano, T., Yamawaki, Y., Kushiyama, A., Sakoda, H., Fujishiro, M., Ryo, A., Ono, H., Minamino, T., Takahashi, SI., Ohno, H., Yoneda, M., Takahashi, K., Ishihara, H., Katagiri, H., Nishimura, F., Kanematsu, T., Yamada, T.,and Asano, T.
  • Journal Title: Cell Rep. Volume: 26 Pages: 3221-3230
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins (2019)
  • Author(s): Inoue, MK., Nakatsu, Y., Yamamotoya, T., Hasei, S., Kanamoto, M., Naitou, M., Matsunaga, Y., Sakoda, H., Fujishiro, M., Ono, H., Kushiyama, A., and Asano, T.
  • Journal Title: Cells Volume: 8 Pages: 1545-1545
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects Against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice. (2019)
  • Author(s): Mizuno, Y., Yamamotoya, T., Nakatsu, Y., Ueda, K., Matsunaga, Y., Inoue, MK., Sakoda, H., Fujishiro, M., Ono, H., Kikuchi, T., Takahashi, M., Morii, K., Sasaki, K., Masaki, T., Asano, T., and Kushiyama, A.
  • Journal Title: Int. J. Mol. Sci. Volume: 20 Pages: 4680-4680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Binds to and Stabilizes Acetyl CoA Carboxylase 1 Protein, Thereby Supporting Cancer Cell Proliferation (2019)
  • Author(s): Ueda, K., Nakatsu, Y., Yamamotoya, T., Ono, H., Inoue, Y., Inoue, MK., Mizuno, Y., Matsunaga, Y., Kushiyama, A., Sakoda, H., Fujishiro, M., Takahashi, SI., Matsubara, A., and Asano, T.
  • Journal Title: Oncotarget Volume: 10 Pages: 1637-1648
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation. (2019)
  • Author(s): Ueda K, Nakatsu Y, Yamamotoya T, Ono H, Inoue Y, Inoue MK, Mizuno Y, Matsunaga Y, Kushiyama A, Sakoda H, Fujishiro M, Takahashi SI, Matsubara A, Asano T.
  • Journal Title: Oncotarget Volume: 10 Pages: 1637-1648
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
  • Journal Title: Cell Rep Volume: 26 Pages: 3221-3230
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model. (2018)
  • Author(s): Inoue MK, Yamamotoya T, Nakatsu Y, Ueda K, Inoue Y, Matsunaga Y, Sakoda H, Fujishiro M, Ono H, Morii K, Sasaki K, Masaki T, Suzuki Y, Asano T, Kushiyama A.
  • Journal Title: Int J Mol Sci Volume: 19
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of Pin1 inhibitors and their potential as therapeutic agents. (2018)
  • Author(s): Nakatsu Y, Matsunaga Y, Ueda K, Yamamotoya T, Inoue Y, Inoue MK, Mizuno Y, Kushiyama A, Ono H, Fujishiro M, Ito H, Okabe T, Asano T.
  • Journal Title: Curr Med Chem Volume: 10 Pages: 2174-2174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line. (2018)
  • Author(s): Furuta H, Yoshihara H, Fukushima T, Yoneyama Y, Ito A, Worrall C, Girnita A, Girnita L, Yoshida M, Asano T, Komada M, Kataoka N, Chida K, Hakuno F, Takahashi SI.
  • Journal Title: Oncotarget Volume: 9 Pages: 33871-33883
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model. (2018)
  • Author(s): Inoue MK, Yamamotoya T, Nakatsu Y, Ueda K, Inoue Y, Matsunaga Y, Sakoda H, Fujishiro M, Ono H, Morii K, Sasaki K, Masaki T, Suzuki Y, Asano T, Kushiyama A.
  • Journal Title: Int J Mol Sci. Volume: 19
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of Pin1 inhibitors and their potential as therapeutic agents. (2018)
  • Author(s): Nakatsu Y, Matsunaga Y, Ueda K, Yamamotoya T, Inoue Y, Inoue MK, Mizuno Y, Kushiyama A, Ono H, Fujishiro M, Ito H, Okabe T, Asano T.
  • Journal Title: Curr Med Chem. Volume: 10 Pages: 2174-2174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 骨格筋Pin1は、運動機能及び糖代謝を制御する (2019)
  • Author(s): 中津 祐介、中井 菜摘、伊藤 輝、山本屋 武、上田 晃司、井上 賢紀、水野 優、味八木 茂、安達 伸生、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] SGLT2阻害薬によるマウス糖尿病性腎障害の改善及び、腎Pin1発現量の是正とAMPK活性化の関与 (2019)
  • Author(s): 井上 賢紀、中津 祐介、松永 泰花、山本屋 武、上田 晃司、井上 由貴、水野 優、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 脂肪細胞のTrk-fused gene (TFG)による代謝制御機構の解明 (2019)
  • Author(s): 山本屋 武、長谷井 俊、中津 祐介、井上 賢紀、迫田 秀之、藤城 緑、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] キサンチンオキシターゼ阻害薬febuxostatによる糖尿病性腎症の改善とその作用機序の解明 (2019)
  • Author(s): 水野 優、中津 祐介、山本屋 武、上田 晃司、井上 賢紀、藤城 緑、迫田 秀之、櫛山 暁史、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] Pin1 and Trk-fused gene (TFG): novel regulators for beta-cell mass and function (2019)
  • Author(s): 山本屋 武、中津 祐介、櫛山 暁史、石原 寿光、浅野 知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] SGLT2阻害薬によるマウス糖尿病性腎障害の改善及び、腎Pin1発現量の是正とAMPK活性化の関与 (2018)
  • Author(s): 井上 賢紀，中津 祐介，松永 泰花，山本屋 武，上田 晃嗣， 井上 由貴，櫛山 暁史，浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] マクロファージにおける糖代謝による活性酸素産生とインスリン抵抗性 (2018)
  • Author(s): 櫛山暁史、菊池貴子、迫田秀之、藤城緑、山本屋武、山崎広貴、中津祐介、浅野地一郎、河津捷二
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] プロリン異性化酵素Pin1による脂肪蓄積制御機構の解明 (2018)
  • Author(s): 中津 祐介，山本屋 武，上田 晃嗣，井上 賢紀，井上 由貴， 櫛山 暁史，浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 2型糖尿病を対象としたキサンチン酸化還元酵素の血管合併症発症および進展に対する影響に関する探索研究 (2018)
  • Author(s): 藤城 緑，櫛山 暁史，山口 賢，渡邉健太郎，江頭富士子， 岡本真由美，村瀬 貴代，中村 敬志，山本屋 武，中津 祐介， 浅野知一郎，石原 寿光
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] Trk-fused gene (TFG) の糖代謝調節における役割の解明 (2018)
  • Author(s): 山本屋 武，中津 祐介，上田 晃嗣，井上 賢紀，迫田 秀之， 藤城 緑，櫛山 暁史，石原 寿光，浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] SGLT2阻害薬によるマウス糖尿病性腎症の改善及び、腎Pin1発現量の是正とAMPK活性化の関与 (2018)
  • Author(s): 井上賢紀、中津祐介、松永泰花、山本屋武、上田晃嗣、井上由貴、櫛山暁史、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] マクロファージにおける糖代謝による活性酸素産生とインスリン抵抗性 (2018)
  • Author(s): 櫛山暁史、菊池貴子、迫田秀之、藤城緑、山本屋武、山崎広貴、中津祐介、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] プロリン異性化酵素Pin1による脂肪蓄積制御機構の解明 (2018)
  • Author(s): 中津祐介、山本屋武、上田晃嗣、井上賢紀、井上由貴、櫛山暁史、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] 2型糖尿病を対象としたキサンチン酸化還元酵素の血管合併症発症および進展に対する影響に関する探索研究 (2018)
  • Author(s): 藤城緑、櫛山暁史、山口賢、渡辺健太郎、江頭富士子、岡本真由美、村瀬貴代、中村敬志、山本屋武、中津祐介、浅野知一郎、石原寿光
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] Trk-fused gene (TFG)の糖代謝調節における役割の解明 (2018)
  • Author(s): 山本屋武、中津祐介、上田晃嗣、井上賢紀、迫田秀之、藤城緑、櫛山暁史、石原寿光、浅野知一郎
  • Organizer: 第61回日本糖尿病学会年次学術集会