Spatiotemporal and metabolic route of essential fatty acid in the brain

• Project/Area Number: 20K08900
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Yanagida Keisuke 国立研究開発法人国立国際医療研究センター, 研究所・脂質生命科学研究部, 上級研究員 (00583882)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ドコサヘキサエン酸 / アラキドン酸 / 多価不飽和脂肪酸 / 脳機能障害 / リピドミクス

Outline of Research at the Start

ドコサヘキサエン酸 (DHA) やアラキドン酸 (ARA)などの多価不飽和脂肪酸は食事からの摂取が必要な必須脂肪酸であり、主に生体膜中のリン脂質に存在する。特にDHAやARAは脳に豊富で、その機能に極めて重要である。しかし、その脳内輸送や分子形態を含む代謝の経路、その生理的意義などについてはほとんどわかっていない。
本研究は、血管から脳実質に取り込まれたDHAやARAなどの必須脂肪酸の脳内時空間的代謝経路を明らかにすることを目的とする。脳内DHA/ARAの低下は様々な脳機能障害に認められており、本研究の成果によりその欠乏や輸送異常による脳機能障害の分子基盤の解明につながることが期待される。

Outline of Final Research Achievements

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are major fatty acids of membrane phospholipid in central nervous system. DHA and ARA are essential fatty acids that cannot be synthesized by mammals, therefore we have to uptake it from diet. However, the spatiotemporal and metabolic route of DHA and ARA into and in the brain as well as their biological significance are incompletely understood. In this study, we assessed the spatiotemporal and metabolic route of DHA/ARA in the brain.
In this study, we found that lysophosphatidylcholine (LPC) incorporated into brain endothelial cells was metabolized into phosphatidylcholine. Also, the results suggested that there is a potential delivery route of DHA/ARA independent of their LPC form. Furthermore, we identified a brain endothelium-specific transcriptional program that is triggered by LPC incorporation.

Academic Significance and Societal Importance of the Research Achievements

DHAやARAの脳への輸送機序やその生理的意義や必須脂肪酸の分子形態を含めた分子基盤の基礎的な理解は不足している。本研究成果により、これまで想定されていたリゾホスファチジルコリン（LPC）による脳への輸送経路とは独立した輸送機構の存在が示唆されたこと、LPCの取り込みが起点となる脳血管内皮細胞特有の遺伝子発現調節機構が同定されたことにより、今後のこの新規輸送経路の同定や遺伝子調節機構の詳細な解析を通じ、神経疾患や脳健康維持のための新しい治療/予防戦略への応用が期待される。

Research Products

• [Journal Article] Dietary omega-3 fatty acid does not improve male infertility caused by lysophospholipid acyltransferase 3 (LPLAT3/AGPAT3) deficiency (2023)
  • Author(s): Nagata Katsuyuki、Kakizaki Yuusuke、Yanagida Keisuke、Arai Tetsuya、Nakano Kenta、Hamano Fumie、Goto Motohito、Okamura Tadashi、Shimizu Takao、Shindou Hideo
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 663 Pages: 179-185
  • DOI: 10.1016/j.bbrc.2023.04.043
  • Peer Reviewed / Open Access
• [Journal Article] Lysophosphatidic acid, a simple phospholipid with myriad functions (2023)
  • Author(s): Yanagida Keisuke、Shimizu Takao
  • Journal Title: Pharmacology & Therapeutics Volume: 246 Pages: 108421-108421
  • DOI: 10.1016/j.pharmthera.2023.108421
  • Peer Reviewed / Open Access
• [Journal Article] Constitutively active GPR43 is crucial for proper leukocyte differentiation (2022)
  • Author(s): Miyasato Sosuke、Iwata Kurumi、Mura Reika、Nakamura Shou、Yanagida Keisuke、Shindou Hideo、Nagata Yosuke、Kawahara Masahiro、Yamaguchi Satoshi、Aoki Junken、Inoue Asuka、Nagamune Teruyuki、Shimizu Takao、Nakamura Motonao
  • Journal Title: The FASEB Journal Volume: 37 Issue: 1 Pages: 1-18
  • DOI: 10.1096/fj.202201591r
  • Peer Reviewed
• [Journal Article] Cell-trafficking impairment in disease-associated LPA6 missense mutants and a potential pharmacoperone therapy for autosomal recessive woolly hair/hypotrichosis (2022)
  • Author(s): Yanagida Keisuke、Masago Kayo、Yasuda Daisuke、Hamano Fumie、Kurikawa Yoshitaka、Shimizu Takao、Ishii Satoshi
  • Journal Title: Human Molecular Genetics Volume: 32 Issue: 5 Pages: 825-834
  • DOI: 10.1093/hmg/ddac244
  • Peer Reviewed
• [Journal Article] Bitter taste receptor T2R38 is expressed on skin-infiltrating lymphocytes and regulates lymphocyte migration (2022)
  • Author(s): Sakakibara Moe、Sumida Hayakazu、Yanagida Keisuke、Miyasato Sosuke、Nakamura Motonao、Sato Shinichi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 11790-11790
  • DOI: 10.1038/s41598-022-15999-6
  • Peer Reviewed / Open Access
• [Journal Article] Update and nomenclature proposal for mammalian lysophospholipid acyltransferases, which create membrane phospholipid diversity (2022)
  • Author(s): Valentine William J.、Yanagida Keisuke、Kawana Hiroki、Kono Nozomu、Noda Nobuo N.、Aoki Junken、Shindou Hideo
  • Journal Title: Journal of Biological Chemistry Volume: 298 Issue: 1 Pages: 101470-101470
  • DOI: 10.1016/j.jbc.2021.101470
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine‐1‐phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy (2021)
  • Author(s): Kawai H, Osawa Y, Matsuda M, Tsunoda T, Yanagida K, Hishikawa D, Okawara M, Sakamoto Y, Shimagaki T, Tsutsui Y, Yoshida Y, Yoshikawa S, Hashi K, Doi H, Mori T, Yamazoe T, Yoshio S, Sugiyama M, Okuzaki D, Komatsu H, Inui A, Tamura-Nakano M, Oyama C, Shindou H, Kusano H, Kage M, Ikegami T, Yanaga K, Kanto T
  • Journal Title: Hepatology Volume: - Issue: 1 Pages: 112-125
  • DOI: 10.1002/hep.32256
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine 1-Phosphate Receptor Signaling Establishes AP-1 Gradients to Allow for Retinal Endothelial Cell Specialization (2020)
  • Author(s): Yanagida Keisuke、Engelbrecht Eric、Niaudet Colin、Jung Bongnam、Gaengel Konstantin、Holton Kristina、Swendeman Steven、Liu Catherine H.、Levesque Michel V.、Kuo Andrew、Fu Zhongjie、Smith Lois E.H.、Betsholtz Christer、Hla Timothy
  • Journal Title: Developmental Cell Volume: 52 Issue: 6 Pages: 779-793.e7
  • DOI: 10.1016/j.devcel.2020.01.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress?dependent VEGF-C signaling (2020)
  • Author(s): Geng Xin、Yanagida Keisuke、Akwii Racheal G.、Choi Dongwon、Chen Lijuan、Ho YenChun、Cha Boksik、Mahamud Md. Riaj、Berman de Ruiz Karen、Ichise Hirotake、Chen Hong、Wythe Joshua、Mikelis Constantinos M.、Hla Timothy、Srinivasan R. Sathish
  • Journal Title: JCI Insight Volume: 5 Issue: 14
  • DOI: 10.1172/jci.insight.137652
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids (2020)
  • Author(s): Hishikawa Daisuke、Yanagida Keisuke、Nagata Katsuyuki、Kanatani Ayumi、Iizuka Yoshiko、Hamano Fumie、Yasuda Megumi、Okamura Tadashi、Shindou Hideo、Shimizu Takao
  • Journal Title: iScience Volume: 23 Issue: 9 Pages: 101495-101495
  • DOI: 10.1016/j.isci.2020.101495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Druggable Lysophospholipid Signaling Pathways (2020)
  • Author(s): Yanagida Keisuke、Valentine William J.
  • Journal Title: Advances in Experimental Medicine and Biology Volume: 1274 Pages: 137-176
  • DOI: 10.1007/978-3-030-50621-6_7
  • ISBN: 9783030506209, 9783030506216
• [Presentation] 遺伝子改変マウスにより迫る脳発達期ドコサヘキサエン酸の意義 (2023)
  • Author(s): 柳田圭介, 叶谷愛弓, 菱川大介, 清水孝雄, 進藤英雄
  • Organizer: 日本農芸化学会 2023年度大会, シンポジウム「非古典的栄養感知による恒常性制御」
• [Presentation] S1P-dependent transcriptional switch between physiological and pathological angiogenesis (2021)
  • Author(s): Keisuke Yanagida
  • Organizer: FASEB Summer Research Conference, The Lysophospholipid and Related Mediators Conference: From Bench to Clinic
  • Int'l Joint Research / Invited
• [Presentation] リゾリン脂質メディエーターの生理機能解明 (2020)
  • Author(s): 柳田圭介
  • Organizer: 第93回 日本生化学会 (2020年度日本生化学会奨励賞受賞講演)
  • Invited
• [Presentation] 血管新生/成熟の協調的進行をもたらすスフィンゴシン1リン酸シグナリング (2020)
  • Author(s): 柳田圭介
  • Organizer: 第93回 日本生化学会