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Research investigating the onset mechanism of peroxisomal disease and the development of new biomarkers from lipid metabolomics

Research Project

Project/Area Number 17K10062
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionTeikyo University

Principal Investigator

Yokoyama Kazuaki  帝京大学, 薬学部, 教授 (50246021)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsペルオキシソーム病 / 先天代謝異常症 / 副腎白質ジストロフィー / 脂質メタボローム / リピトミクス / スフィンゴ糖脂質の網羅的解析 / アシルCoAの網羅的解析 / 分子種分析 / リピドミクス / リン脂質の網羅的解析 / 脂質 / 遺伝病 / メタボローム / バイオマーカー
Outline of Final Research Achievements

An increase in the level of very long chain fatty acids (VLCFAs) was observed because of adrenoleukodystrophy, a peroxisomal disease, which is caused by a mutation in the ABCD1 gene. This study aimed to elucidate the onset mechanism and biomarkers of this disease from three perspectives. First, comprehensive molecular analysis systems were established for sphingomyelin and acyl-CoA, an intermediate of phospholipid synthesis. VLCFAs accumulated at the sn-1 position of phospholipids and levels of C26:1-CoA increased in the fibroblasts of patients. Second, several acyltransferases were identified as enzymes potentially responsible for the biosynthesis of VLCFA-containing phospholipids using ABCD1-deficient cells that were designed by gene editing. Third, the multichannel MRM analysis system for the comprehensive molecular analysis of glycosphingolipids was established using a chiral column and LC-MS.

Academic Significance and Societal Importance of the Research Achievements

副腎白質ジストロフィーでは発症機構の解明と発症の前兆のバイオマーカーの発見が期待されている。本研究では従来十分な解析法がなかったスフィンゴミエリン、アシルCoA、スフィンゴ糖脂質について網羅的解析法を樹立したことで、新たに詳細なリピドミクスを行うことが可能となった。極長鎖脂肪酸をグリセロール1位に持つリン脂質やC26:1-CoAが顕著に蓄積することが明らかとなった。またリン脂質のグリセロール1位へ極長鎖脂肪酸を導入する酵素の解明が進んだ。これらにより病態の新たな一端が明らかとなり、発症の前兆となるバイオマーカーの発見の手筈も整ったといえる。臨床応用に向けてはさらなる研究の推進が必要である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (28 results)

All 2020 2019 2018 2017

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (22 results) (of which Int'l Joint Research: 3 results) Book (1 results)

  • [Journal Article] Hexacosenoyl-CoA is the most abundant very long-chain acyl-CoA in ATP binding cassette transporter D1-deficient cells2020

    • Author(s)
      Hama K, Fujiwara Y, Takashima S, Hayashi Y, Yamashita A, Shimozawa N, Yokoyama K.
    • Journal Title

      J Lipid Res.

      Volume: 61 Issue: 4 Pages: 523

    • DOI

      10.1194/jlr.p119000325

    • URL

      https://localhost/en/publications/24d341fe-7d47-4ee4-b549-20a177dfbc05

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mass spectrometry in combination with a chiral column and multichannel-MRM allows comprehensive analysis of glycosphingolipid molecular species from mouse brain2020

    • Author(s)
      Fujiwara Yuko、Hama Kotaro、Yokoyama Kazuaki
    • Journal Title

      Carbohydrate Research

      Volume: 490 Pages: 107959-107959

    • DOI

      10.1016/j.carres.2020.107959

    • URL

      https://pure.teikyo.jp/en/publications/f6340133-0973-4df7-ae19-6f530a40009a

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Quantitative and qualitative method for sphingomyelin by LC-MS using two stable isotopically labeled sphingomyelin species2018

    • Author(s)
      Hama Kotaro、Fujiwara Yuko、Yokoyama Kazuaki
    • Journal Title

      Journal of visualized experiment

      Volume: 2018 Issue: 135

    • DOI

      10.3791/57293

    • URL

      https://pure.teikyo.jp/en/publications/9b01aa19-c579-4fe4-9abb-df84dd26f0dc

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Profiling and Imaging of Phospholipids in Brains of Abcd1-Deficient Mice2018

    • Author(s)
      Hama K, Fujiwara Y, Morita M, Yamazaki F, Nakashima Y, Takei S, Takashima S, Setou M, Shimozawa N, Imanaka T, Yokoyama K.
    • Journal Title

      Lipids

      Volume: 53 Issue: 1 Pages: 85

    • DOI

      10.1002/lipd.12022

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comprehensive Quantitation Using Two Stable Isotopically Labeled Species and Direct Detection of N-Acyl Moiety of Sphingomyelin2017

    • Author(s)
      Hama K, Fujiwara Y, Tabata H, Takahashi H, Yokoyama K.
    • Journal Title

      Lipids

      Volume: 52 Issue: 9 Pages: 789

    • DOI

      10.1007/s11745-017-4279-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Hexacosenoyl-CoA is the most abundantly accumulated very long chain fatty acyl-CoA and increased by bezafibrate in ABCD1-deficient cells2019

    • Author(s)
      Kotaro Hama, Yuko Fujiwara, Shigeo Takashima, Atsushi Yamashita, Yasuhiro Hayashi, Nobuyuki Shimozawa, Kazuaki Yokoyama
    • Organizer
      60th International Conference on the Bioscience of Lipids
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A novel LC-MS/MS method for the comprehensive quantitative analysis of molecular species of glycosphingolipids using a chiral column2019

    • Author(s)
      Yuko Fujiwara, Kotaro Hama, Kazuaki Yokoyama
    • Organizer
      60th International Conference on the Bioscience of Lipids
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] キラルカラムを用いたLC-MS法によるスフィンゴ糖脂質一斉分析系の構築2019

    • Author(s)
      藤原優子, 濱弘太郎, 横山和明
    • Organizer
      第38回日本糖質学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] キラルカラムを用いたスフィンゴ糖脂質一斉分析系によるヒドロキシ脂肪酸分子種の解析2019

    • Author(s)
      藤原優子, 濱弘太郎, 横山和明
    • Organizer
      第38回日本糖質学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] BezafibrateはABCD1欠損条件下において極長鎖脂肪酸CoAを上昇させる2019

    • Author(s)
      濱弘太郎, 藤原優子, 高島茂雄, 下澤伸行, 横山和明
    • Organizer
      第61回日本脂質生化学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] キラルカラムを用いたLC-MS一斉分析系によるマウス脳スフィンゴ糖脂質の解析2019

    • Author(s)
      藤原優子, 濱弘太郎, 横山和明
    • Organizer
      第44回日本医用マススペクトル学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞内の極長鎖脂肪酸脂肪酸CoA量を上昇する薬剤の検証2019

    • Author(s)
      濱弘太郎, 藤原優子, 高島茂雄, 下澤伸行, 横山和明
    • Organizer
      第92回日本生化学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] キラルカラムを用いたスフィンゴ糖脂質のLC-MS一斉分析系によるマウス脳の解析2019

    • Author(s)
      藤原優子, 濱弘太郎, 横山和明
    • Organizer
      第61回日本先天代謝異常学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Lorenzo's oilとBezafibrateの極長鎖脂肪酸脂肪酸CoAに対する影響2019

    • Author(s)
      濱弘太郎, 藤原優子, 高島茂雄, 下澤伸行, 横山和明
    • Organizer
      第61回日本先天代謝異常学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ロレンツォオイル添加時の各種極長鎖脂肪酸脂肪酸CoAの定量2018

    • Author(s)
      濱弘太郎、藤原優子、山下純、横山和明
    • Organizer
      第60回日本脂質生化学会
    • Related Report
      2018 Research-status Report
  • [Presentation] キラルカラムを用いたヒドロキシ脂肪酸含有スフィンゴ糖脂質の解析2018

    • Author(s)
      藤原 優子、濱 弘太郎、横山 和明
    • Organizer
      第60回日本脂質生化学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Quantitation of each acyl-CoA species in ABCD1-deficient cells2018

    • Author(s)
      Kotaro Hama, Yuko Fujiwara, Atsushi Yamashita and Kazuaki Yokoyama
    • Organizer
      59th international conference on the bioscience of lipids
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] キラルカラムによるLC-MSを用いたヒドロキシ脂肪酸含有スフィンゴ糖脂質の解析2018

    • Author(s)
      藤原 優子、濱 弘太郎、横山 和明
    • Organizer
      第43回日本医用マススペクトル学会
    • Related Report
      2018 Research-status Report
  • [Presentation] キラルカラムを用いたヒドロキシ脂肪酸含有スフィンゴ糖脂質の解析2018

    • Author(s)
      藤原 優子、濱 弘太郎、横山 和明
    • Organizer
      第60回日本先天代謝異常学会
    • Related Report
      2018 Research-status Report
  • [Presentation] ABCD1ノックアウト細胞における極長鎖脂肪酸CoAの定量2017

    • Author(s)
      濱弘太郎、藤原優子、山下純、横山和明
    • Organizer
      第59回脂質生化学会
    • Related Report
      2017 Research-status Report
  • [Presentation] スフィンゴ糖脂質を対象とする網羅的解析の為のキラルカラムによる分離系 の検討2017

    • Author(s)
      藤原 優子、濱 弘太郎、横山 和明
    • Organizer
      第59回脂質生化学会
    • Related Report
      2017 Research-status Report
  • [Presentation] ABCD1ノックアウト細胞における極長鎖脂肪酸CoAの定量2017

    • Author(s)
      濱弘太郎、藤原優子、山下純、横山和明
    • Organizer
      第42回日本医用マススペクトル学会
    • Related Report
      2017 Research-status Report
  • [Presentation] LC-ESI-MSを用いたスフィンゴ糖脂質の網羅的解析の為のキラルカラムによる分離系の検討と生体サンプルへの適用2017

    • Author(s)
      藤原 優子、濱 弘太郎、横山 和明
    • Organizer
      第42回日本医用マススペクトル学会
    • Related Report
      2017 Research-status Report
  • [Presentation] ABCD1欠損細胞中の極長鎖脂肪酸CoAの定量2017

    • Author(s)
      濱弘太郎、藤原優子、山下純、横山和明
    • Organizer
      第59回先天代謝異常学会
    • Related Report
      2017 Research-status Report
  • [Presentation] キラルカラムを用いた生体サンプル中のスフィンゴ糖脂質の解析2017

    • Author(s)
      藤原 優子、濱 弘太郎、横山 和明
    • Organizer
      第59回先天代謝異常学会
    • Related Report
      2017 Research-status Report
  • [Presentation] ABCD1ノックアウト細胞における極長鎖脂肪酸CoAの定量2017

    • Author(s)
      濱弘太郎、藤原優子、山下純、横山和明
    • Organizer
      生命科学系学会合同年次大会(ConBio2017)
    • Related Report
      2017 Research-status Report
  • [Presentation] キラルカラムを用いた生体サンプル中のスフィンゴ糖脂質の解析2017

    • Author(s)
      藤原 優子、濱 弘太郎、横山 和明
    • Organizer
      生命科学系学会合同年次大会(ConBio2017)
    • Related Report
      2017 Research-status Report
  • [Book] Peroxisomes: Biogenesis, Function, and Role in Human Disease2019

    • Author(s)
      Hama K, Fujiwara Y, Yokoyama K.
    • Publisher
      Springer
    • Related Report
      2019 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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