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Mechanism of enhanced hepatotoxicity through fatty acid metabolic imbalance in the progression of fatty liver disease

Research Project

Project/Area Number 20K08315
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionJuntendo University

Principal Investigator

Kon Kazuyoshi  順天堂大学, 医学部, 先任准教授 (30398672)

Co-Investigator(Kenkyū-buntansha) 池嶋 健一  順天堂大学, 医学部, 教授 (20317382)
李 賢哲  順天堂大学, 医学部, 助教 (30758321)
千葉 麻子  順天堂大学, 医学部, 准教授 (40532726)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords脂肪毒性 / 脂肪酸不飽和化酵素 / 非アルコール性脂肪肝炎 / 肝がん / 肝線維化 / 抗酸化物質 / 肝癌 / ケモカイン / 酸化ストレス / グリシン / PTEN / 自然免疫 / アミノ酸 / 脂質合成 / 脂肪酸代謝 / アルコール性肝障害
Outline of Research at the Start

脂肪性肝疾患、特に非アルコール性脂肪肝炎“NASH”の罹患数は増加しており、病態機序の解明による予防・治療法の確立が急務である。飽和脂肪酸およびトランス脂肪酸の摂取がNASHの増悪因子とされているが、脂肪酸は代謝によって様々な構造を呈するため、脂肪酸の分子構造の変化がどのように脂肪毒性(細胞障害)の亢進に働くのかは不明であった。本研究では、脂肪酸代謝不均衡による脂肪酸の構造変化と脂肪毒性の増悪による脂肪性肝疾患の病態進展機序を明らかにすることにより、新規診断・治療法の開発を目指すものである。

Outline of Final Research Achievements

To investigate the induction mechanism and effects of lipotoxicity in the progression of fatty liver disease, we conducted studies using animal models mimicking some processes of fatty liver disease. Mice with imbalance in lipid metabolism by reduction of fatty acid desaturase 2 showed exacerbation of steatohepatitis and hepatic fibrosis due to a high-fat/high-cholesterol diet. Hepatocyte-specific PTEN knockout mice, a model of steatohepatitis-associated liver carcinogenesis, exhibited a decrease in antioxidants and an increase in inflammatory cytokines during the process from steatohepatitis to hepatocellular carcinogenesis, all which were suppressed by glycine administration. In addition, anti-tumor immunity was also enhanced and hepatocarcinogenesis was significantly reduced by glycine. It was suggested that lipid metabolism imbalance contributes to exacerbation of steatohepatitis, and that lipotoxicity impairs antitumor immunity and leads to hepatocarcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、脂肪酸代謝の変調による脂肪毒性の増加が脂肪肝炎を増悪させ、肝線維化を亢進させることが明らかになり、加齢に伴う脂肪肝炎増悪のメカニズムの一端が明確になった。脂肪酸代謝酵素の評価が脂肪肝炎増悪リスクのスクリーニングに有用である可能性、脂肪酸代謝酵素を標的とした新規治療法の可能性が示され、現在の脂肪肝炎のもつ諸問題の解決に重要な知見を得ることができた。さらに抗腫瘍免疫の制御に脂肪毒性の関与が示唆されたことは重要であり、脂肪肝炎の重大な予後規定因子である肝発がんの早期発見および治療法の確立に寄与しうる学術的意義の大きな結果が得られた。

Report

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

    (12 results)

All 2023 2022 2021

All Presentation (12 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results)

  • [Presentation] Downregulation of fatty acid desaturase 2 exacerbates murine steatohepatitis caused by high-fat and high-cholesterol diet.2023

    • Author(s)
      Kon K, Lee-Okada HC, Arai K, Uchiyama A, Sato T, Fukada H, Yamashina S, Ikejima K.
    • Organizer
      Digestive Disease Week 2023.
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Amino acid glycine suppresses steatohepatitis and tumorigenesis in hepatocyte-specific phosphatase and tensin homolog knockout mice.2022

    • Author(s)
      Kon K, Arai K, Uchiyama A, Fukada H, Sato T, Morinaga M, Fukuhara K, Yaginuma R, Yamashina S, Ikejima K.
    • Organizer
      International Liver Congress 2022 of the European Association for the Study of the Liver (EASL).
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Glycine supplementation inhibits steatohepatitis-related liver carcinogenesis in hepatocyte-specific PTEN deficient mice.2022

    • Author(s)
      Kon K, Arai K, Uchiyama A, Yaginuma R, Sato T, Yamashina S, Ikejima K.
    • Organizer
      American Association for the Study of Liver Disease (AASLD) The Liver Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Glycine Intake Ameliorates Steatohepatitis and Prevents Liver Carcinogenesis in Hepatocyte-specific Pten-deficient Mice.2022

    • Author(s)
      Kon K.
    • Organizer
      The Asian Pacific Association for the Study of the Liver (APASL) Oncology 2022.
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脂肪肝炎形成の分子機構とジェントロジー.2022

    • Author(s)
      今一義,石塚敬,池嶋健一.
    • Organizer
      合同シンポジウム1(日本肝臓学会)「脂質異常症と脂肪肝のクロストーク」.第54回日本動脈硬化学会総会・学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Glycine ameliorates steatohepatitis via reduction of oxidative stress in hepatocyte-specific PTEN-deficient mice.2021

    • Author(s)
      Kon K, Arai K, Uchiyama A, Fukada H, Nakadera E, Yaginuma R, Fukuhara K, Yamashina S, Ikejima K.
    • Organizer
      The Asian Pacific Association for the Study of the Liver (APASL) Single Topic Conference.
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Amino acid prevents tumorigenesis via ameliorating steatohepatitis in hepatocyte-specific phosphatase and tensin homolog knockout mice.2021

    • Author(s)
      Kon K, Arai K, Uchiyama A, Fukada H, Nakadera E, Morinaga M, Fukuhara K, Yaginuma R, Yamashina S, Ikejima K.
    • Organizer
      American Association for the Study of Liver Disease (AASLD) The Liver Meeting
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] アミノ酸グリシンによる脂肪肝炎の改善効果―肝特異的PTENノックアウトマウスを用いた検討-.2021

    • Author(s)
      今一義、新井久美子、内山明、深田浩大、中寺英介、山科俊平、池嶋健一.
    • Organizer
      第58回日本消化器免疫学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 肝細胞特異的PTENノックアウトマウスにおけるグリシンの脂肪肝炎・肝がん抑制効果.2021

    • Author(s)
      今一義、山科俊平、池嶋健一.
    • Organizer
      第22回JDDW(第25回日本肝臓学会大会)ワークショップ11.
    • Related Report
      2021 Research-status Report
  • [Presentation] 肝特異的PTEN欠損脂肪肝炎モデルマウスにおける アミノ酸グリシンの効果2021

    • Author(s)
      今一義,山科俊平,池嶋健一
    • Organizer
      第107回 日本消化器病学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] アミノ酸グリシンによる脂肪肝炎の改善効果―肝特異的PTENノックアウトマウスを用いた検討-2021

    • Author(s)
      今一義、新井久美子、内山明、深田浩大、中寺英介、山科俊平、池嶋健一
    • Organizer
      第58回 日本消化器免疫学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 肝細胞特異的PTENノックアウトマウスにおけるグリシンの脂肪肝炎・肝がん抑制効果2021

    • Author(s)
      今一義,山科俊平,池嶋健一
    • Organizer
      Japan Digestive Disease Week 2021
    • Related Report
      2020 Research-status Report

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

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