Study aiming for the development of NASH prevention focusing on lipoxygenase

• Project/Area Number: 16K08916
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Okayama Prefectural University
• Principal Investigator: Takahashi Yoshitaka 岡山県立大学, 保健福祉学部, 教授 (10236333)
• Co-Investigator(Kenkyū-buntansha): 川上 祐生 岡山県立大学, 保健福祉学部, 准教授 (30453202)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 12-リポキシゲナーゼ / 非アルコール性脂肪性肝炎 / 肝臓 / アラキドン酸 / 肝星細胞 / リポキシゲナーゼ / 薬理学 / 食品

Outline of Final Research Achievements

The catalytic activity of 12S-lipoxygenase was clearly detectable in liver cytosol of NASH model mice prepared by feeding a methionine and choline-deficient (MCD) diet. The product profile, substrate specificity and immunogenicity indicated that the enzyme was the platelet-type isoform. The expression levels of mRNA and protein of platelet-type 12S-lipoxygenase were significantly increased as compared with those of normal chow-fed mice. Immunohistochemical analysis showed that platelet-type 12S-lipoxygenase colocalized with alpha-smooth muscle actin as well as vitamin A in the cells distributing along liver sinusoids. These results indicate that the expression level of platelet-type 12S-lipoxygenase in hepatic stellate cells was increased during the cell activation in MCD diet-fed mice,.

Academic Significance and Societal Importance of the Research Achievements

慢性炎症肝において線維化の主役として働く肝星細胞に血小板型12-リポキシゲナーゼの局在が証明され、線維化の進行に伴って本酵素が誘導される可能性が示唆されたことは、本酵素が慢性炎症性肝疾患における線維化の進行において何らかの重要な役割を果たすことを強く示唆しており、今後この役割が解明されれば、慢性炎症性肝疾患の予後の決定因子の一つである線維化の予防につながると考えられ、学術的社会的意義は大きい。

Research Products

• [Journal Article] Arachidonate 12S-lipoxygenase of platelet-type in hepatic stellate cells of methionine and choline-deficient diet-fed mice (2020)
  • Author(s): Mori Yoshiko、Kawakami Yuki、Kanzaki Keita、Otsuki Akemi、Kimura Yuka、Kanji Hibiki、Tanaka Ryoma、Tsukayama Izumi、Hojo Nana、Suzuki-Yamamoto Toshiko、Kawakami Takayo、Takahashi Yoshitaka
  • Journal Title: The Journal of Biochemistry Volume: - Pages: 455-463
  • DOI: 10.1093/jb/mvaa062
  • NAID: 40022409777
  • Peer Reviewed / Open Access
• [Journal Article] Red-kerneled rice proanthocyanidin inhibits arachidonate 5-lipoxygenase and decreases psoriasis-like skin inflammation (2020)
  • Author(s): Toda Keisuke、Tsukayama Izumi、Nagasaki Yuki、Konoike Yuka、Tamenobu Asako、Ganeko Natsuki、Ito Hideyuki、Kawakami Yuki、Takahashi Yoshitaka、Miki Yoshimi、Yamamoto Kei、Murakami Makoto、Suzuki-Yamamoto Toshiko
  • Journal Title: Arch Biochem Biophys. Volume: - Pages: 108307-108307
  • DOI: 10.1016/j.abb.2020.108307
  • Peer Reviewed / Open Access
• [Journal Article] Ellagitannins from Punica granatum leaves suppress microsomal prostaglandin E synthase-1 expression and induce lung cancer cells to undergo apoptosis. (2020)
  • Author(s): Keisuke Toda, Mai Ueyama, Shomu Tanaka, Izumi Tsukayama, Takuto Mega, Yuka Konoike, Asako Tamenobu, Februadi Bastian, Iria Akai, Hideyuki Ito, Yuki Kawakami, Yoshitaka Takahashi, Toshiko Suzuki-Yamamoto.
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 84 Pages: 757-763
  • DOI: 10.1080/09168451.2019.1706442
  • Peer Reviewed / Open Access
• [Journal Article] Ingestion of soy protein isolate attenuates eccentric contraction-induced force depression and muscle proteolysis via inhibition of calpain-1 activation in rat fast-twitch skeletal muscle (2019)
  • Author(s): Kanzaki Keita、Watanabe Daiki、Aibara Chihiro、Kawakami Yuki、Yamada Takashi、Takahashi Yoshitaka、Wada Masanobu
  • Journal Title: Nutrition Volume: 58 Pages: 23-29
  • DOI: 10.1016/j.nut.2018.06.025
  • Peer Reviewed
• [Journal Article] Involvement of the Hydroperoxy Group in the Irreversible Inhibition of Leukocyte-Type 12-Lipoxygenase by Monoterpene Glycosides Contained in the Qing Shan Lu Shui Tea (2019)
  • Author(s): Kawakami Yuki、Otsuki Akemi、Mori Yoshiko、Kanzaki Keita、Suzuki-Yamamoto Toshiko、Fang Ding、Ito Hideyuki、Takahashi Yoshitaka
  • Journal Title: Molecules Volume: 24 Pages: 304-304
  • DOI: 10.3390/molecules24020304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] l-arginine ingestion inhibits eccentric contraction-induced proteolysis and force deficit via S-nitrosylation of calpain (2018)
  • Author(s): Kanzaki Keita、Watanabe Daiki、Aibara Chihiro、Kawakami Yuki、Yamada Takashi、Takahashi Yoshitaka、Wada Masanobu
  • Journal Title: Physiol Rep Volume: 6
  • DOI: 10.14814/phy2.13582
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preventive effect of <i>Dioscorea japonica</i> on squamous cell carcinoma of mouse skin involving down-regulation of prostaglandin E₂ synthetic pathway (2018)
  • Author(s): Tsukayama I, Toda K, Takeda Y, Mega T, Tanaka M, Kawakami Y, Takahashi Y, Kimoto M, Yamamoto K, Miki Y, Murakami M, Suzuki-Yamamoto T.
  • Journal Title: J. Clin. Biochem. Nutr. Volume: 62 Issue: 2 Pages: 139-147
  • DOI: 10.3164/jcbn.17-54
  • NAID: 130006407477
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Y54(L)W mutation of anti-leukotriene C4 single-chain antibody increases affinity to leukotriene E4 (2017)
  • Author(s): Yuki Kawakami, Mai Kinoshita, Yoshiko Mori, Shuji Okochi, Shiori Hirano, Ichika Shimoda, Keita Kanzaki, Toshiko Suzuki-Yamamoto, Masumi Kimoto, Mitsuaki Sugahara, Tetsuya Hori, Hiromichi Saino, Masashi Miyano, Shozo Yamamoto, Yoshitaka Takahashi.
  • Journal Title: J. Biochem. Volume: 161 Pages: 79-86
  • DOI: 10.1093/jb/mvw055
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular Cloning of Rat acss3 and Characterization of Mammalian Propionyl-CoA Synthetase in the Liver Mitochondrial Matrix (2017)
  • Author(s): Y. Yoshimura, A. Araki, H. Maruta, Y. Takahashi, and H. Yamashita
  • Journal Title: J. Biochem. Volume: 161 Pages: 279-289
  • DOI: 10.1093/jb/mvw067
  • NAID: 40021162084
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Activation of AMP-Activated Protein Kinase and Stimulation of Energy Metabolism by Acetic Acid in L6 Myotube Cells. (2016)
  • Author(s): H. Maruta, Y. Yoshimura, A. Araki, M. Kimoto, Y. Takahashi, and H. Yamashita
  • Journal Title: PLOS ONE. Volume: 11 Pages: 1-19
  • DOI: 10.1371/journal.pone.0158055
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] チェリー・オブ・ザ・リオ・グランデ葉抽出物による5-リポキシゲナーゼ阻害 (2020)
  • Author(s): 川上祐生、神崎真由香、桐岡佐妃、津嘉山泉、岩岡裕二、伊東秀之、山本登志子、高橋吉孝
  • Organizer: 日本農芸化学会2020年度大会
• [Presentation] 非アルコール性脂肪性肝炎で上昇する12-リポキシゲナーゼアイソザイム (2019)
  • Author(s): 森香子、川上祐生、神崎圭太、大槻朱美、木村優花、神治響、田中龍舞、津嘉山泉、北條奈々、山本登志子、川上貴代、高橋吉孝
  • Organizer: 第92回日本生化学会大会
• [Presentation] Monoterpene glycosides from Qing Shan Lu Shui tea irreversibly inhibit the catalytic activity of leukocyte-type 12-lipoxygenase (2019)
  • Author(s): uki Kawakami, Akemi Otsuki, Yoshiko Mor, Keita Kanzaki, Toshiko Suzuki-Yamamoto, Ding Zhi Fang, Hideyuki Ito, Yoshitaka Takahashi
  • Organizer: ICBL2019
  • Int'l Joint Research
• [Presentation] 5-リポキシゲナーゼ活性を抑制するナツメグ含有成分による気管支喘息の軽減作用 (2018)
  • Author(s): 川上祐生、森香子、戸田圭祐、神崎圭太、山本登志子、伊東秀之、高橋吉孝
  • Organizer: _第72回日本栄養・食糧学会大会
• [Presentation] Mutations of anti-leukotriene C4 single-chain antibody change the antigen binding specificity (2018)
  • Author(s): Yuki Kawakami, Mai Kinoshita, Yoshiko Mori, Shuji Okochi, Shiori Hirano, Keita Kanzaki, Toshiko Suzuki-Yamamoto, Masumi Kimoto, Mitsuaki Sugahara, Tetsuya Hori, Hiromichi Saino, Masashi Miyano, Yoshitaka Takahashi
  • Organizer: BAO2018
  • Int'l Joint Research
• [Presentation] Catalytic activity of 12-lipoxygenase immunoprecipitated by an antibody against platelet-type 12-lipoxygenase in liver cytosol prepared from NASH model mice (2017)
  • Author(s): Yoshiko Mori1, Yuki Kawakami1, Keita Kanzaki2, Toshiko Suzuki-Yamamoto1,
  • Organizer: 58ｔｈ ICBL2017
  • Int'l Joint Research
• [Presentation] Mutations of anti-leukotriene C4 single-chain antibody that change the antigen binding specificity (2017)
  • Author(s): Yuki Kawakami 1, Mai Kinoshita 1, Yoshiko Mori 1, Shuji Okochi 1, Toshiko Suzuki-Yamamoto 1, Mitsuaki Sugahara 2, Tetsuya Hori 2, Hiromichi Saino 3, Masashi Miyano 2,3, Yoshitaka Takahashi 1
  • Organizer: 58ｔｈ ICBL2017
  • Int'l Joint Research
• [Presentation] 抗ロイコトリエンC4単鎖抗体の変異体による抗原結合特異性の変化 (2017)
  • Author(s): 川上祐生1、金山友紀1、新庄望良野1、神崎圭太1、山本登志子1、菅原光明2、齊野廣道3、宮野雅司2,3、山本尚三4、高橋吉孝1
  • Organizer: 第59回日本脂質生化学会
• [Presentation] 非アルコール性脂肪性肝炎モデルマウス肝における血小板型12S-リポキシゲナーゼの発現上昇 (2016)
  • Author(s): 森 香子、大槻 朱美、川上 祐生、神崎 圭太、山本 登志子、川上 貴代、木本 眞順美、山下 広美、高橋 吉孝、
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-25
• [Presentation] 非アルコール性脂肪性肝炎進展における12-リポキシゲナーゼの役割 (2016)
  • Author(s): 森 香子、大槻 朱美、川上 祐生、神崎 圭太、山本 登志子、川上 貴代、木本 眞順美、山下 広美、辻 英明、高橋 吉孝
  • Organizer: 第７０回日本栄養・食糧学会大会
  • Place of Presentation: 武庫川女子大学
  • Year and Date: 2016-05-13
• [Presentation] Identification of 12-lipoxygenase isozyme in NASH model mice (2016)
  • Author(s): Yoshiko Mori, Keita Kanzaki, Yuki Kawakami, Toshiko Suzuki-Yamamoto, Hiromi Yamashita, Yoshitaka Takahashi
  • Organizer: The 10th Joint Conference on Nutrition and Food Science
  • Place of Presentation: Woosong University, Daejeon, Korea
  • Int'l Joint Research