Endogenous choline production through phospholipid catabolism

• Project/Area Number: 18K06978
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: HIRABAYASHI Tetsuya 公益財団法人東京都医学総合研究所, 基礎医科学研究分野, 主席研究員 (90345025)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: コリン / グリセロホスホコリン / リゾホスホリパーゼ / メチル基 / 肝臓 / 神経変性 / ホスホリパーゼA2 / リン脂質 / 筋萎縮 / ホスファチジルコリン / リン脂質分解 / メタボロミクス

Outline of Final Research Achievements

We have shown that the iPLA2gamma/iPLA2theta/glycerophosphoesterase axis functions as an intrinsic choline production pathway that mobilizes free choline from the membrane phospholipids to supply methyl groups in the liver. This pathway is necessary for the methionine regeneration and normal liver function. Moreover, CNS-specific iPLA2delta and iPLA2theta deficiency causes profound neuronal degeneration and muscle atrophy, indicating that these lysohpspholipases have crucial roles in the survival of neurons including motor neurons.

Academic Significance and Societal Importance of the Research Achievements

本研究で明らかとした肝臓と神経系における内因性コリン産生系の役割は、脂肪肝、神経変性、筋萎縮などの疾患群とリン脂質代謝経路の関連性を示唆し、従来想定されていたリゾホスホリパーゼの概念を大きく転換するものである。将来的にリン脂質分解酵素の機能介入を通じて肝機能、神経機能、骨格筋機能を人為的に調節できるようになれば、新しい分子機序に基づく健康食品・医薬品の開発に結びつくことが期待される。

Research Products

• [Int'l Joint Research] Vanderbilt大学(米国)
• [Int'l Joint Research] University of Alberta(米国)
• [Journal Article] Group IVE cytosolic phospholipase A2 limits psoriatic inflammation by mobilizing the anti‐inflammatory lipid N‐acylethanolamine. (2022)
  • Author(s): Liang Luyiyun、Takamiya Rina、Miki Yoshimi、Heike Kanako、Taketomi Yoshitaka、Sugimoto Nao、Yamaguchi Midori、Shitara Hiroshi、Nishito Yasumasa、Kobayashi Tetsuyuki、Hirabayashi Tetsuya、Murakami Makoto
  • Journal Title: The FASEB Journal Volume: 36 Issue: 5
  • DOI: 10.1096/fj.202101958r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation (2020)
  • Author(s): Takeichi T, Hirabayashi T, Miyasaka Y, Kawamoto A, Okuno Y, Taguchi S, Tanahashi K, Murase C, Takama H, Tanaka K, Boeglin WE, Calcutt MW, Watanabe D, Kono M, Muro Y, Ishikawa J, Ohno T, Brash AR, Akiyama M
  • Journal Title: J Clin Invest Volume: 130 Issue: 2 Pages: 890-903
  • DOI: 10.1172/jci130675
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling. (2019)
  • Author(s): Mori A, Hatano T, Inoshita T, Shiba-Fukushima K, Koinuma T, Meng H, Kubo SI, Spratt S, Cui C, Yamashita C, Miki Y, Yamamoto K, Hirabayashi T, Murakami M, Takahashi Y, Shindou H, Nonaka T, Hasegawa M, Okuzumi A, Imai Y, Hattori N.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116(41) Issue: 41 Pages: 20689-20699
  • DOI: 10.1073/pnas.1902958116
  • NAID: 120007132272
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The role of PNPLA1 in ω-O-acylceramide synthesis and skin barrier function (2019)
  • Author(s): Hirabayashi Tetsuya、Murakami Makoto、Kihara Akio
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids Volume: 1864 Issue: 6 Pages: 869-879
  • DOI: 10.1016/j.bbalip.2018.09.010
  • Peer Reviewed / Open Access
• [Journal Article] iPLA2/PNPLAファミリーがかかわる脂質代謝異常と疾患 (2018)
  • Author(s): 平林哲也
  • Journal Title: 医学のあゆみ Volume: 264 Pages: 149-154
• [Journal Article] ホスホリパーゼA2ファミリーによるリポクオリティ制御 (2018)
  • Author(s): 村上誠、佐藤弘泰、武富芳隆、平林哲也
  • Journal Title: 実験医学 Volume: 36 Pages: 1623-1630
• [Presentation] 肝臓のリン脂質分解を介したメチル基供給とトリグリセリド産生 (2021)
  • Author(s): 平林 哲也、川口 舞、笠原 浩二、村上 誠
  • Organizer: 第28回肝細胞研究会
• [Presentation] 中枢神経系における PNPLA6および PNPLA7欠損は筋萎縮を伴う神経変性を生じる (2021)
  • Author(s): 川口 舞、笠原 浩二、村上 誠、平林 哲也
  • Organizer: 第94回日本生化学会大会
• [Presentation] SDR9C7 catalyzes the critical dehydrogenation of acylceramides for skin barrier formation (2021)
  • Author(s): T Takeichi, T Hirabayashi, Y Miyasaka, A Kawamoto, Y Okuno, S Taguchi, K Tanahashi, C Murase, H Takama, K Tanaka, W Boeglin, M Calcutt, D Watanabe, M Kono, Y Muro, J Ishikawa, T Ohno, AR Brash and M Akiyama
  • Organizer: Society for Investigative Dermatology 2021
  • Int'l Joint Research
• [Presentation] Phosphatidylcholine breakdown by PNPLA8 and PNPLA7 supplies methyl groups in the liver (2019)
  • Author(s): Mai Kawaguchi, Tetsuya Hirabayashi, Makoto Murakami
  • Organizer: 60th International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] The lysophospholipase PNPLA7 is induced by methionine depletion and is linked to epigenetic regulation (2019)
  • Author(s): Sayaka Harada, Yoshitaka Taketomi, Mai Kawaguchi, Tetsuya Hirabayashi, Makoto Murakami
  • Organizer: 60th International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] Group IVE phospholipase A2 (cPLAε) mobilizes the non-canonical lipid mediator N-acylethanolamine in mouse skin (2019)
  • Author(s): Luyiyun Liang, Kanako Heike, Tetsuyuki Kobayashi, Tetsuya Hirabayashi, Yoshimi Miki, Kei Yamamoto, Yoshitaka Taketomi, Makoto Murakami
  • Organizer: 60th International Conference on the Bioscience of Lipids
  • Int'l Joint Research
• [Presentation] PNPLA8, PNPLA7を介した内因性コリン産生経路は肝臓のメチル基供給に寄与する (2019)
  • Author(s): 川口舞、平林哲也、笠原浩二、村上誠
  • Organizer: 第61回日本脂質生化学会
• [Presentation] 皮膚における新規細胞質型ホスホリパーゼA2(cPLA2ε, cPLA2δ)の機能解析 (2019)
  • Author(s): 梁 陸伊韻, 三木 寿美, 平林 哲也, 平家 圭奈子, 小林 哲幸, 山本 圭, 武富 芳隆, 高宮 里奈, 村上 誠
  • Organizer: 第92回日本生化学会大会
• [Presentation] A new enzyme in the 12R-lipoxygenase pathway, vital for the role of EFA in skin barrier function (2019)
  • Author(s): Alan R Brash, Takuya Takeichi, William E Boeglin, James A Weiny, M Wade Calcutt, Tetsuya Hirabayashi, Masashi Akiyama
  • Organizer: 16th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases
  • Int'l Joint Research
• [Presentation] アシルセラミド代謝を介した皮膚バリア形成機構 (2019)
  • Author(s): 平林哲也, 武市拓也, 笠原浩二, Alan R. Brash, 村上 誠, 秋山真志
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Phosphatidylcholine catabolism by PNPLA7 provides a source of hepatic methyl groups and controls energy homeostasis (2018)
  • Author(s): Tetsuya Hirabayashi, Makoto Murakami
  • Organizer: 59th ICBL (International Conference on the Bioscience of Lipids)
  • Int'l Joint Research
• [Presentation] Phosphatidylcholine catabolism mediated by PNPLAs plays an important role in liver function and energy homeostasis (2018)
  • Author(s): Tetsuya Hirabayashi, Makoto Murakami
  • Organizer: 2nd Japan-Korea Lipid Joint Symposium
  • Int'l Joint Research
• [Presentation] PNPLA8とPNPLA7によるホスファチジルコリンの分解は肝臓のメチル基供給に重要である (2018)
  • Author(s): 川口舞、平林哲也、村上誠
  • Organizer: 第91回日本生化学会大会
• [Remarks] 細胞膜研究室 研究業績
  • URL: https://www.igakuken.or.jp/biomembrane/publication.html
• [Remarks] (公財)東京都医学総合研究所 基礎医科学研究分野 細胞膜研究室
  • URL: https://www.igakuken.or.jp/biomembrane/Study.html
• [Remarks] 東京都医学総合研究所 TOPICS 2019
  • URL: http://www.igakuken.or.jp/topics/2019/1106.html
• [Patent(Industrial Property Rights)] 神経変性及び筋委縮モデル動物 (2021)
  • Inventor(s): 平林哲也、村上誠
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-173338
  • Filing Date: 2021