Analysis of mechanism by which tetrandrine modulates lipid degradation via blockade of autophagy

• Project/Area Number: 26870309
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Bioorganic chemistry; Biomolecular chemistry
• Research Institution: University of Tsukuba (2016); Kyoto University (2014-2015)
• Principal Investigator: MIYAMAE Yusaku 筑波大学, 生命環境系, 准教授 (30610240)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: オートファジー / 脂肪滴 / テトランドリン / perilipin / 肝線維化 / 標的分子

Outline of Final Research Achievements

Autophagy is a cellular quality control system which degrades unnecessary proteins and organelles. In this study, we analyzed the mechanism by which tetrandrine, a plant-derived isoquinoline alkaloid, modulates lipid degradation via blockade of autophagy. We showed that the compound inhibits the autophagy pathway without affecting lysosomal function. A phenotypic comparison using siRNA knockdown suggested that tetrandrine may target regulators, involved in fusion between autophagosomes and lysosomes. Moreover, perilipin, an lipid droplet (LD)-coated protein, co-localized specifically with LC3, a marker protein for autophagosomes, in tetrandrine-treated cells. This suggests a potential role for perilipin in autophagy-mediated LD degradation.

Research Products

• [Journal Article] The isoflavone fraction from soybean presents mRNA maturation inhibition activity (2017)
  • Author(s): Kurata M, Murata Y, Momma K, Fouad Ali Mursi I, Takahashi M, Miyamae Y, Kambe T, Nagao M, Narita H, Shibuya Y, Masuda S
  • Journal Title: Biosci Biotechnol Biochem Volume: 81 Issue: 3 Pages: 551-554
  • DOI: 10.1080/09168451.2016.1249451
  • Peer Reviewed / Open Access
• [Journal Article] Structure-Activity Relationship of Phenylpropanoid Glycosides on the Inhibition of Amyloid β (2016)
  • Author(s): Kidachi, E.; Kurisu, M.; Miyamae, Y.; Hanaki, M.; Murakami, K.; Irie, K.; Shigemori, H.
  • Journal Title: Heterocycles Volume: 92 Issue: 11 Pages: 1976-1982
  • DOI: 10.3987/com-16-13533
  • Peer Reviewed
• [Journal Article] The PP-motif in luminal loop 2 of ZnT transporters plays a pivotal role in TNAP activation (2016)
  • Author(s): Fujimoto S, Tsuji T, Fujiwara T, Takeda T, Merriman C, Fukunaka A, Nishito Y, Fu D, Hoch E, Sekler I, Fukue K, Miyamae Y, Masuda S, Nagao M, Kambe T
  • Journal Title: Biochem. J Volume: 473 Issue: 17 Pages: 2611-2621
  • DOI: 10.1042/bcj20160324
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tetrandrine induces lipid accumulation through blockade of autophagy in a hepatic stellate cell line (2016)
  • Author(s): Miyamae Y, Nishito Y, Nakai N, Nagumo Y, Usui T, Masuda S, Kambe T, Nagao M
  • Journal Title: Biochem Biophys Res Commun Volume: 477 Issue: 1 Pages: 40-46
  • DOI: 10.1016/j.bbrc.2016.06.018
  • Peer Reviewed / Open Access
• [Journal Article] 核内受容体PPARγのユニークな特性と新奇リガンド開発への新展開 (2016)
  • Author(s): 宮前友策、永尾雅哉
  • Journal Title: 化学と生物 Volume: 54 Pages: 791-793
  • Peer Reviewed
• [Journal Article] Identification of a new type of covalent PPARγ agonist using a ligand-linking strategy (2015)
  • Author(s): Ohtera, A., Miyamae, Y.*, Yoshida, K., Maejima, K., Akita, T., Kakizuka, A., Irie, K., Masuda, S., Kambe, T., Nagao, M.
  • Journal Title: ACS Chemical Biology Volume: 10 Issue: 12 Pages: 2794-2804
  • DOI: 10.1021/acschembio.5b00628
  • Peer Reviewed / Open Access
• [Journal Article] Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting (2015)
  • Author(s): 2)Hashimoto, A., Ohkura, K., Takahashi, M., Kizu, K., Narita, H., Enomoto, S., Miyamae, Y., Masuda, S., Nagao, M., Irie, K., Ohigashi, H., Andrews, G. K., Kambe, T.
  • Journal Title: Biochemical Journal Volume: 472 Issue: 2 Pages: 183-193
  • DOI: 10.1042/bj20150862
  • NAID: 120006305978
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] オートファジー阻害剤テトランドリンの新規作用機序 (2015)
  • Author(s): ○宮前友策、西藤有希奈、仲井奈緒美、増田誠司、神戸大朋、永尾雅哉
  • Organizer: 第57回天然有機化合物討論会
  • Place of Presentation: 神奈川県民ホール
  • Year and Date: 2015-09-09
• [Presentation] リガンド結合ポケットの特性を利用した新規共有結合性PPARγアゴニストの創製 (2015)
  • Author(s): ○宮前友策、大寺杏奈、吉田光多郎、前嶋一宏、秋田徹、垣塚彰、入江一浩、増田誠司、神戸大朋、永尾雅哉
  • Organizer: 第10回日本ケミカルバイオロジー学会
  • Place of Presentation: 東北大学
  • Year and Date: 2015-06-10
• [Presentation] Cooperative activation of PPARgamma by combination of irreversible antagonist and partial agonists: implication for novel activation mechanism based on covalent modification (2014)
  • Author(s): Yusaku Miyamae, Anna Ohtera, Kotaro Yoshida, Toru Akita, Kazuhiro Maejima, Akira Kakizuka, Kazuhiro Irie, Seiji Masuda, Taiho Kambe, Masaya Nagao
  • Organizer: International Chemical Biology Society, 3rd annual meeting
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2014-11-17 – 2014-11-19
• [Presentation] 肝線維化抑制物質テトランドリンによるオートファジー経路制御機構の解明 (2014)
  • Author(s): 西藤有希奈、宮前友策、仲井奈緒美、Han Junkyu、礒田博子、増田誠司、神戸大朋、永尾雅哉
  • Organizer: 第９回日本ケミカルバイオロジー学会
  • Place of Presentation: 大阪大学
  • Year and Date: 2014-06-11 – 2014-06-13