Analysis of biological function regulated by membrane phospholipid diversity

• Project/Area Number: 26460380
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: SHINDOU Hideo 国立研究開発法人国立国際医療研究センター, その他部局等, 副プロジェクト長 (10401027)
• Co-Investigator(Renkei-kenkyūsha): HISHIKAWA Daisuke 国立国際医療研究センター, 上級研究員 (10569966) ; YOSHIDA Tomomi 国立国際医療研究センター, 上級研究員 (30610216) ; HARAYAMA Takeshi 国立国際医療研究センター, 研究員 (50610218) ; HISHIKAWA Yoshiko 国立国際医療研究センター, 脂質シグナリングプロジェクト, 研究員 (60436574) ; TARUI Megumi 国立国際医療研究センター, 研究員 (40727749)
• Research Collaborator: YANAGIDA Keisuke ; VALENTINE William ; TAKAHASHI Yoshikazu ; NAGATA Katsuyuki ; Eto Miki ; MORIMOTO Ryo ; AMEMIYA Ami ; TODORIKI Naruha ; ITO Hiroshi
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 生化学 / リン脂質 / 生体膜 / リゾリン脂質アシル転移酵素 / 脂質メディエーター

Outline of Final Research Achievements

Membrane glycerophospholipids are important not only as structural and functional components of cellular membranes, but also as precursors of various lipid mediators, such as platelet-activating factor (PAF). In this study, we reported three phospholipid functions. (i) Dipalmitoylphosphatidylcholine (DPPC) produced by lysophosphatidylcholine acyltransferase 1 (LPCAT1) is important for respiratory function. (ii) Platelet-activating factor (PAF) by LPCAT2 exacerbated neuropathic pain. (iii) Arachidonic acid containing phospholipid by LPCAT3 were needed for triacylglycerol secretion. Molecular mechanism of LPCAT2 activation and screening of LPCAT2 inhibitor were also reported. Additionally, we established a new method to visualize lipid in cells.

Research Products

• [Int'l Joint Research] CNRS(フランス)
• [Int'l Joint Research] ジュネーブ大学(スイス)
• [Journal Article] Relief from neuropathic pain by blocking of platelet-activating factor-pain loop. (2017)
  • Author(s): Shindou, H.*, Shiraishi, S.*, Tokuoka, M. S., Takahashi, Y., Harayama, T., Abe, T., Bando, K., Miyano, K., Kita, Y., Uezono, Y., Shimizu, T.
  • Journal Title: FASEB J. Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury (2016)
  • Author(s): Shigematsu, M., Koga, T., Ishimori, A., Saeki, K., Ishii, Y., Taketomi, Y., Ohba, M., Jo-Watanabe, A., Okuno, T., Harada, N., Harayama, T., Shindou, H., Li, J. D., Murakami, M., Hoka, S.,Yokomizo, T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34560-34560
  • DOI: 10.1038/srep34560
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Blood-brain barrier permeability of ginkgolide: Comparison of the behavior of PET probes 7a-[18F]fluoro- and 10-O-p-[11C]methylbenzyl ginkgolide B in monkey and rat brains. (2016)
  • Author(s): Doi, H., Sato, K., Shindou, H., Sumi, K., Koyama, H., Hosoya, T., Watanabe, Y., Ishii, S., Tsukada, H., Nakanishi, K., and Suzuki, M.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 21 Pages: 5148-5157
  • DOI: 10.1016/j.bmc.2016.08.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Imaging of Intracellular Fatty Acids by Scanning X-ray Fluorescence Microscopy. (2016)
  • Author(s): Shimura, M., Shindou, H, Szyrwiel, L., Tokuoka, M.S., Hamano, F., Matsuyama, S., Okamoto, M., Matsunaga, A., Kita, Y., Ishizaka, Y., Yamauchi, K., Komura, Y., Lobinski, R., Shimizu, I., Shimizu, T. *, equal contribution
#, equal corresponding author
  • Journal Title: FASEB J. Volume: 30 Issue: 12 Pages: 4149-4158
  • DOI: 10.1096/fj.201600569r
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Lysophosphatidylethanolamina acyltransfcrase/membrane-bound O-acyltransferase 1 regulates morphology and function of P19C6 cell-derived neurons. (2016)
  • Author(s): Tabe S， Hikiji H， Ariyoshi W， Hashidate-Yoshida T， Shindou H，Okinaga T， Shimizu T， Tominaga K，Nishihara T.
  • Journal Title: FASEB. J Volume: 30 Issue: 7 Pages: 2591-2601
  • DOI: 10.1096/fj.201500097r
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lysophosphatidylcholine acyltransferase 1 protects against cytotoxicity induced by polyunsaturated fatty acids. (2016)
  • Author(s): Akagi, S., Kono, N., Ariyama, H., Shindou, H., Shimizu, T., and Arai, H.
  • Journal Title: FASEB J. Volume: 30 Issue: 5 Pages: 2027-2039
  • DOI: 10.1096/fj.201500149
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] From zero to six double bonds: phospholipid unsaturation and organelle functions. (2015)
  • Author(s): Antonny B., Vanni, S., Shindou H., and Ferreira T.
  • Journal Title: Trends in Cell Biology Volume: 25 Pages: 427-436
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Essential Role of Lysophosphatidylcholine Acyltransferase 3 in the Induction of Macrophage Polarization in PMA-Treated U937 Cells (2015)
  • Author(s): Taniguchi K, Hikiji H, Okinaga T, Hashidate-Yoshida T, Shindou H, Ariyoshi W, Shimizu T, Tominaga K, Nishihara T
  • Journal Title: J Cell Biochem Volume: 116 Issue: 12 Pages: 2840-2848
  • DOI: 10.1002/jcb.25230
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Establishment of LC-MS method for the analysis of palmitoylated surfactant proteins. (2015)
  • Author(s): Harayama, T., Shindou, H., Kita, Y., Otsubo, E., Ikeda, K., Chiba, S., Weaver, T. and Shimizu, T.
  • Journal Title: J. Lipid Res. Volume: 56 Issue: 7 Pages: 1370-1379
  • DOI: 10.1194/jlr.d060236
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role of p38 mitogen-activated protein kinase in linking stearoyl-CoA desaturase-1 activity with ER homeostasis. (2015)
  • Author(s): Koeberle, A., Pergola, C., Shindou, H., Koeberle, SC., Shimizu, T., Laufer, SA., and Werz O.
  • Journal Title: FASEB J Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells. (2014)
  • Author(s): Hishikawa, D., Hashidate, T., Shimizu, T., and Shindou, H.
  • Journal Title: J. Lipid Res. Volume: 55 Issue: 5 Pages: 799-807
  • DOI: 10.1194/jlr.r046094
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rapid Production of Platelet-activating Factor Is Induced by Protein Kinase Cα-mediated Phosphorylation of Lysophosphatidylcholine Acyltransferase 2. (2014)
  • Author(s): Morimoto, R., Shindou, H., Tarui, M., and Shimizu, T.
  • Journal Title: J. Biol. Chem. Volume: in press Issue: 22 Pages: 15566-15576
  • DOI: 10.1074/jbc.m114.558874
  • Peer Reviewed / Open Access
• [Journal Article] elective inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2 (2014)
  • Author(s): Tarui, M., Shindou, H., Kumagai, K., Morimoto, R., Harayama, T., Hashidate, T., Kojima, H., Okabe, T., Nagano, T., Nagase, T., and Shimizu, T.
  • Journal Title: J. Lipid Res. Volume: 55 Issue: 7 Pages: 1386-1396
  • DOI: 10.1194/jlr.m049205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo (2014)
  • Author(s): Takeshi Harayama, Miki Eto, Hideo Shindou, Yoshihiro Kita, Eiji Otshubo, Daisuke Hishikawa, Satoshi Ishii, Kenji Sakimura, Masayoshi Mishina and Takao Shimizu
  • Journal Title: Cell Metabolism Volume: 20 Issue: 2 Pages: 295-305
  • DOI: 10.1016/j.cmet.2014.05.019
  • Peer Reviewed / Open Access
• [Journal Article] Fatty acyl-chain remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport.
  • Author(s): Hashidate-Yoshida T., Harayama T., Hishikawa D., Morimoto R., Hamano F., Mitamura-Tokuoka S., Eto M., Tamura-Nakano M., Yanobu-Takanashi R., Mukumoto Y., Kiyonari H., Okamura T., Kita Y., Shindou H., and Shimizu T.
  • Journal Title: eLife Volume: 21 Pages: 06328-06328
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ２種の機能性リン脂質解析：血小板活性化因子と神経因性疼痛・DHAリン脂質と視覚機能 (2017)
  • Author(s): 進藤英雄
  • Organizer: 第５回生体情報研究シンポジウム
  • Place of Presentation: 秋田市
  • Invited
• [Presentation] 細胞内脂肪酸運命の可視化 (2016)
  • Author(s): 進藤英雄、志村まり、Lukasz Szyrwiel、岡本真由美、浜野文三江、徳岡涼美、北芳博、清水功雄、清水孝雄
  • Organizer: 日本脂質生化学会
  • Place of Presentation: 秋田市
  • Year and Date: 2016-06-09
• [Presentation] Lysophospholipid acyltransferases (LPLATs) modulate lipid compositions of cellular membranes during myoblast differentiation (2016)
  • Author(s): William Valentine, Hideo Shindou, Daisuke Hishikawa, and Takao Shimizu
  • Organizer: 日本脂質生化学会
  • Place of Presentation: 東京都
  • Year and Date: 2016-05-28
• [Presentation] リゾホスファチジルコリンアシル転移酵素3(LPCAT3)によるトリアシルグリセロール輸送の調節 (2016)
  • Author(s): 橋立智美、原山武士、菱川大介、森本亮、浜野文三江、徳岡涼美、衛藤樹、北芳博、進藤英雄、清水孝雄
  • Organizer: 日本脂質生化学会
  • Place of Presentation: 東京都
  • Year and Date: 2016-05-28
• [Presentation] 生体膜リン脂質制御による視覚機能制御の解明 (2016)
  • Author(s): 進藤英雄
  • Organizer: 平成27年度東京大学医科学研究所共同研究拠点事業報告会
  • Place of Presentation: 東京都
  • Year and Date: 2016-03-15
  • Invited
• [Presentation] 一元素ラベルによる細胞内脂肪酸運命の可視化 (2016)
  • Author(s): 進藤英雄
  • Organizer: 第１５回ホスファチジルセリン研究会
  • Place of Presentation: 早稲田大学 日本橋
  • Invited
• [Presentation] Platelet-activating factor and eicosanoid regulation by LPCAT2~Relationship to neuropathic pain~ (2015)
  • Author(s): 進藤英雄
  • Organizer: 第88回日本生化学会大会シンポジウム（BMB2015）
  • Place of Presentation: 兵庫県
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] 生体機能に寄与する生体膜リン脂質の多様性形成：リゾリン脂質アシル転移酵素欠損マウスの表現系より (2015)
  • Author(s): 進藤英雄
  • Organizer: 群馬大学第１回生体調節研究所内分泌代謝シンポジウム
  • Place of Presentation: 群馬県
  • Year and Date: 2015-11-12
  • Invited
• [Presentation] IPAを活用した生体膜リン脂質代謝解析～ようやくわかってきた生体膜多様性形成の分子メカニズム～ (2015)
  • Author(s): 進藤英雄
  • Organizer: Ingenuityユーザーグループミーティング
  • Place of Presentation: 東京都
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] 生体膜脂質の多様性形成と多様な役割 (2015)
  • Author(s): 進藤英雄
  • Organizer: 第９回レドックス・ライフイノベーションシンポジウム
  • Place of Presentation: 理研横浜
  • Year and Date: 2015-03-13 – 2015-03-14
  • Invited
• [Presentation] 生体膜リン脂質脂肪酸多様性形成メカニズムの解析 (2015)
  • Author(s): 進藤英雄
  • Organizer: 第２回JFAS
  • Place of Presentation: 東京秋葉原AKIBAホール
  • Year and Date: 2015-02-15
  • Invited
• [Presentation] Lysophosphatidic acid acyltransferase 4 (LPAAT4), a novel enzyme with activity for incorporating DHA into glycerophospholipids (2015)
  • Author(s): Miki Eto, Hideo Shindou, Takao Shimizu
  • Organizer: 6th International Conference on Phospholipase A2 and Lipid Mediators
  • Place of Presentation: 新宿 京王プラザホテル東京
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] dentification of lysophosphatidic acid acyltransferase 4 (LPAAT4), a possible role for incorporating DHA into glycerophospholipids (2014)
  • Author(s): Miki Eto, Hideo Shindou, Takao Shimizu
  • Organizer: Max Planck-The University of Tokyo Center Symposium 2014
  • Place of Presentation: Berlin
  • Year and Date: 2014-12-17
• [Presentation] 生体膜リン脂質生合成メカニズム～ようやくわかってきた生体膜多様性形成の分子メカニズム～ (2014)
  • Author(s): 進藤英雄
  • Organizer: 文部科学省大学間連携共同教育推進事業 地域連携による「ものづくり」継承支援人材育成協働プロジェクト
  • Place of Presentation: 九州歯科大学
  • Year and Date: 2014-11-27
  • Invited
• [Presentation] Membrane remodeling by lysophospholipid acyltransferases (2014)
  • Author(s): Hideo Shindou and Takao Shimizu
  • Organizer: Conferences Jacques Monod
  • Place of Presentation: Roscoff (Brittany), France
  • Year and Date: 2014-11-15 – 2014-11-19
  • Invited
• [Presentation] ドコサヘキサエノイル-CoA (DHA-CoA) 特異的新規リゾホスファチジン酸アシル転移酵素LPAAT4の同定およびアルツハイマー病との関連についての解析 (2014)
  • Author(s): 衛藤樹, 橋本唯史, 進藤英雄, 岩坪威, 清水孝雄
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-17
• [Presentation] 新規肺胞腔内脂質結合タンパク質Sec14-like 3の生化学的機能解析 (2014)
  • Author(s): 菱川大介, 進藤英雄, 原山武士, 小笠原理恵, 諏訪部章, 清水孝雄
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-16
• [Presentation] 生体膜リン脂質多様性形成メカニズム (2014)
  • Author(s): 進藤 英雄, 森本 亮, 垂井 愛, 衛藤 樹, 原山 武士, 清水 孝雄
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-15
  • Invited
• [Presentation] Identification of novel pulmonary surfactant lipid-related protein, Sec14-like 3 (2014)
  • Author(s): Daisuke Hishikawa, Hideo Shindou, Takeshi Harayama, Rie Ogasawara, Akira Suwabe, and Takao Shimizu
  • Organizer: FASEB
  • Place of Presentation: Vermont Academy Saxtons River, Vermont, USA
  • Year and Date: 2014-07-27 – 2014-08-01
• [Presentation] Identification of a novel lysophosphatidic acid acyltransferase enzyme (LPAAT4) with preference for polyunsaturated fatty acyl-CoA (2014)
  • Author(s): Miki Eto, Hideo Shindou, Takao Shimizu
  • Organizer: 55th International Conference on the Bioscience of Lipids: Lipids as Mediators of Health and Disease
  • Place of Presentation: University of Aberdeen Aberdeen AB24 3FX Scotland
  • Year and Date: 2014-06-23 – 2014-06-27
• [Presentation] Phosphorylated lysophosphatidylcholine acyltransferase 2 (LPCAT2) mediates rapid platelet-activating factor (PAF) production following PAF- or ATP-stimulation in macrophages (2014)
  • Author(s): Ryo Morimoto, Hideo Shindou, Megumi Tarui, Takao Shimizu
  • Organizer: 55th International Conference on the Bioscience of Lipids: Lipids as Mediators of Health and Disease
  • Place of Presentation: University of Aberdeen Aberdeen AB24 3FX Scotland
  • Year and Date: 2014-06-23 – 2014-06-27
• [Presentation] 新規肺胞腔内分泌タンパク質Sec14-like 3の生化学的機能解析 (2014)
  • Author(s): 菱川大介、進藤英雄、清水孝雄
  • Organizer: 第13回 肺サーファクタント分子病態研究会
  • Place of Presentation: 札幌医科大学 記念ホール
  • Year and Date: 2014-06-21
• [Presentation] PKCαを介した血小板活性化因子合成酵素LPCAT2のリン酸化 (2014)
  • Author(s): 森本 亮、進藤 英雄、垂井 愛、清水 孝雄
  • Organizer: 第56回 日本脂質生化学会
  • Place of Presentation: 近畿大学 東大阪キャンパス
  • Year and Date: 2014-06-07
• [Presentation] High-throughput screeningによるPAF生合成酵素（LPCAT2）阻害剤の同定 (2014)
  • Author(s): 垂井 愛、進藤 英雄、森本 亮、原山 武士、橋立 智美、熊谷 和夫、長野 哲雄、長瀬 隆英、清水 孝雄
  • Organizer: 第56回 日本脂質生化学会
  • Place of Presentation: 近畿大学 東大阪キャンパス
  • Year and Date: 2014-06-07
• [Presentation] 多価不飽和脂肪酸含有リン脂質合成に関わる新規リゾホスファチジン酸アシル転移酵素(LPAAT4)の同定 (2014)
  • Author(s): 衛藤 樹、進藤 英雄、清水 孝雄
  • Organizer: 第56回 日本脂質生化学会
  • Place of Presentation: 近畿大学 東大阪キャンパス
  • Year and Date: 2014-06-06
• [Presentation] Rapid phosphorylation and activation of lysophosphatidylcholine acyltransferase 2 via protein kinase c (2014)
  • Author(s): Hideo Shindou, Ryo Morimoto, Megumi Tarui, Takao Shimizu
  • Organizer: FASEB
  • Place of Presentation: Sheraton At The Falls 300 3rd Street Niagara Falls, NY14303
  • Year and Date: 2014-06-01 – 2014-06-06
• [Book] Lysophospholipid acyltransferases. Bioactive Lipid Mediators: Current Reviews and Protocols. (2015)
  • Author(s): Shindou H., Harayama T., and Hishikawa D.
  • Total Pages: 19
  • Publisher: Springer
• [Book] 循環Plus (2015)
  • Author(s): 進藤英雄
  • Total Pages: 3
  • Publisher: メディカルトリビューン
• [Book] 分子呼吸器病 (2015)
  • Author(s): 菱川大介、進藤英雄、原山武士、小笠原理恵、諏訪部章、清水孝雄
  • Total Pages: 4
  • Publisher: 先端医学社
• [Book] 日本肺サーファクタント・界面医学会雑誌 (2014)
  • Author(s): 小笠原理恵、小笠原勝利、松浦絵里、石田欣二、菱川大介、進藤英雄、清水孝雄、遠山稿二郎、諏訪部章
  • Total Pages: 1
  • Publisher: 日本肺サーファクタント・界面医学会
• [Book] 日本肺サーファクタント・界面医学会雑誌 (2014)
  • Author(s): 進藤英雄
  • Total Pages: 7
  • Publisher: 日本肺サーファクタント・界面医学会
• [Book] 医学のあゆみ (2014)
  • Author(s): 進藤英雄
  • Total Pages: 5
  • Publisher: 医歯薬出版
• [Remarks] 進藤英雄のWebページ
  • URL: http://www.ncgmlipidsp.jp/members/1.html