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Regulatory mechanisms of fatty acids synthesis and breadown in pressure-overloaded heart

Research Project

Project/Area Number 20H03671
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionGunma University

Principal Investigator

Kurabayashi Masahiko  群馬大学, その他部局等, 名誉教授 (00215047)

Co-Investigator(Kenkyū-buntansha) 磯 達也  群馬大学, 大学院医学系研究科, 非常勤講師 (10400756)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2021: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2020: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Keywordsエネルギー代謝 / 脂肪酸 / 遺伝子発現 / ケトン体 / 酸化ストレス / 脂肪酸酸化 / 抗酸化遺伝子 / FGF21 / 心筋代謝 / 心肥大 / 心不全 / 脂肪酸代謝 / 脂肪酸合成 / 膜脂質組成 / ミトコンドリア
Outline of Research at the Start

これまでの研究から、心不全において、FGF21とケトン体(βOHB)の代謝が密接に関連し、これらはPPARシグナルの活性化作用を介して、心筋保護に働く可能性があるという発想に至った。本研究では、心筋における脂肪酸の酸化と合成の調節や脂肪酸の質の調節の分子メカニズムとして、FGF21とβOHBによるAMPK/PPAR経路が関与している可能性を解析する。この仮説を検証するため、FGF21欠損マウスの表現型の解析およびAAVベクターを用いたFGF21の補充による心機能改善効果の有無を解析する。

Outline of Final Research Achievements

The heart is the most energy-demanding and metabolically omnivorous organ which uses ketone bodies as well as fatty acids and glucose as fuel source. It is a growing appreciation that circulating ketone body (bOHB) is not just used during fasting and exercise, but also has important cellular signaling roles to regulate gene expression. Stimulation of neonatal rat cardiomyocytes with bOHB and FGF21 induced peroxisome proliferator-activated receptor-a(PPARa and PGC1a expression along with the phosphorylation of LKB1 and AMPK. bOHB and FGF21 induced transcription of peroxisome proliferator-activated receptor response element (PPRE)-containing genes through an activation of PPARa. Additionally,bOHB and FGF21 induced the expression of Nrf2, a master regulator for oxidative stress response, and catalase and Ucp2 genes.These findings suggest that bOHB and circulating FGF21 coordinately regulate oxidative stress response gene expression in the heart.

Academic Significance and Societal Importance of the Research Achievements

心臓は生体で最もエネルギー産生が活発な臓器であり、脂肪酸酸化によるATP産生が全ATP産生の70%を占める。そのため、脂肪酸の酸化と合成は心臓の機能を維持する上で重要である。私たちは脂肪酸伸長酵素が細胞膜のリン脂質中の脂肪酸組成の決定に大きな役割を持つことを明らかにした。また、エネルギー枯渇に対する適応として肝臓で産生されるケトン体が、脂肪酸の燃焼・酸化を調節するかを検討した結果、ケトン体およびFGF21が脂肪酸酸化に重要な転写因子PPARaと転写コファクタPGC-1aの発現を増加し、抗酸化機能を増強させることを示した。ケトン体とFGF21が心不全治療における新たな治療方法になる可能性がある。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (12 results)

All 2022 2021

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (8 results)

  • [Journal Article] Ketone body and FGF21 coordinately regulate fastibg-induced oxidative stress response in the heart2022

    • Author(s)
      Ryo Kawakami, Hiroaki Sunaga, Tatsuya Iso, Ryosuke Kaneko, Norimichi Koitabashi, Masaru Obokata, Tomonari Harada, Hiroki Matsui, Tomoyuki Yokoyama, Masahiko KUrabayashi
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 7338-7338

    • DOI

      10.1038/s41598-022-10993-4

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport2021

    • Author(s)
      Iso Tatsuya、Kurabayashi Masahiko
    • Journal Title

      Metabolites

      Volume: 11 Issue: 12 Pages: 889-889

    • DOI

      10.3390/metabo11120889

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice2021

    • Author(s)
      Umbarawan Yogi、Kawakami Ryo、Syamsunarno Mas、Obinata Hideru、Yamaguchi Aiko、Hanaoka Hirofumi、Hishiki Takako、Hayakawa Noriyo、Koitabashi Norimichi、Sunaga Hiroaki、Matsui Hiroki、Kurabayashi Masahiko、Iso Tatsuya
    • Journal Title

      Metabolites

      Volume: 11 Issue: 12 Pages: 881-881

    • DOI

      10.3390/metabo11120881

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pathophysiological and diagnostic importance of fatty acid-binding protein 1 in heart failure with preserved ejection fraction2021

    • Author(s)
      Harada Tomonari、Araki Takeshi、Sunaga Hiroaki、Kagami Kazuki、Yoshida Kuniko、Kato Toshimitsu、Kawakami Ryo、Tomono Junichi、Wada Naoki、Iso Tatsuya、Kurabayashi Masahiko、Obokata Masaru
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 21175-21175

    • DOI

      10.1038/s41598-021-00760-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Unappreciated mechanisms of fatty acid uptake in the kidney:Faty acids are taken up from both basolateral and apical side2022

    • Author(s)
      Kawakami R
    • Organizer
      第86回日本循環器学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Cardiac growth and hypertrophic response require exogenous fatty acid uptake, but not endogenous de novo lipogenesis.2021

    • Author(s)
      Ryo Kawakami、T. Iso, H Sunaga, H Mtasui, M. Kurabayashi
    • Organizer
      第85回日本循環器学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Limited FA use by CD36 deficiency accelerates the development of diabetic cardiomyopathy.2021

    • Author(s)
      Ryo Kawakami , Y Umbarawan, T Iso, N Koitabashi, H Sunaga, H Matsui, M Kurabayashi
    • Organizer
      第85回日本循環器学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Fasting-induced ketone body and FGF2 regulate PPArg signaling to restrain oxiative stress in the heart.2021

    • Author(s)
      Ryo Kawakami, H Sunaga, T Iso, N Koitabashi, M Obokata, T Harada, H Matsui, T Yokoyama, M Kurabayashi
    • Organizer
      第85回日本循環器学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Cardiac growth and hypertrophic response require exogenous fatty acid uptake, but not endogenous de novo lipogenesis2021

    • Author(s)
      Ryo Kawakami, Tatsuya Iso, Hiroaki Sunaga, Hiroki Matsui, Norimichi Koitabashi, Masahiko Kurabayashi
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Mitochondrial-related Gene Dysregulation and Spontaneous Cardiomyopathy in Mybpc3-Variant Knock-in Mice2021

    • Author(s)
      Ryo Kawakami, Norimichi Koitabashi, Hideki Uosaki, Hiroaki Sunaga, Hiroki Matsui, Tatsuya Iso, Masahiko Kurabayashi
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Limited Fatty Acid Use by CD36 Deficiency Accelerates the Development of Diabetic Cardiomyopathy2021

    • Author(s)
      Ryo Kawakami, Yogi Umbarawan, Tatsuya Iso, Norimichi Koitabashi, Hiroaki Sunaga, Hiroki Matsui, Masahiko Kurabayashi
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] FABP1 is a novel biomarker for heart failure: A potential mechanism2021

    • Author(s)
      Ryo Kawakami, Hiroaki Sunaga, Tatsuya Iso, Masaru Obokata, Tomonari Harada, Hiroki Matsui, Norimichi Koitabashi, Tomoyuki Yokoyama, and Masahiko Kurabayashi
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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