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Elucidation of novel mechanism for hepatoprotection by iron overload

Research Project

Project/Area Number 20K06415
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 42020:Veterinary medical science-related
Research InstitutionOsaka Metropolitan University (2022)
Osaka Prefecture University (2020-2021)

Principal Investigator

Izawa Takeshi  大阪公立大学, 大学院獣医学研究科, 准教授 (20580369)

Co-Investigator(Kenkyū-buntansha) 竹中 重雄  大阪公立大学, 大学院生活科学研究科, 教授 (10280067)
桑村 充  大阪公立大学, 大学院獣医学研究科, 教授 (20244668)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords慢性肝疾患 / 肝鉄過剰 / 肝毒性 / 脂肪性肝疾患 / 細胞死 / 脂肪肝 / 炎症 / マクロファージ / 鉄過剰 / 薬物性肝障害 / 細胞保護機構 / 薬剤性肝障害 / 細胞保護作用
Outline of Research at the Start

従来,肝鉄過剰は肝疾患の増悪因子と考えられてきたが,申請者らは鉄過剰による肝保護作用が存在する可能性を示してきた.本研究では,標的部位の異なる複数の肝疾患モデル動物を作製し,その病態をモデル間で比較解析することで,鉄過剰による肝保護機構の解明に取り組む.特に,細胞死に中心的な役割を果たすミトコンドリアの機能異常,ストレス応答や解毒代謝経路を調節するNrf-2の役割に注目して,解析を行う.

Outline of Final Research Achievements

Our previous study revealed that hepatic iron overload can cause both exacerbation and suppression of liver diseases; however, the mechanism remains to be elucidated. The present study showed that hepatic iron overload can alter susceptibility to acute hepatotoxicity. Considering the presence of iron overload for the selection of therapeutic options would lead to more safe and effective therapy in patients with chronic liver diseases. Additionally, the present study raised the possibility that hepatic iron overload may worsen dyslipidemia and steatohepatitis in patients with nonalcoholic fatty liver disease. Development of new therapeutic strategies targeting iron dysregulation and macrophage activation is anticipated.

Academic Significance and Societal Importance of the Research Achievements

慢性肝疾患における肝鉄過剰の役割には未だ不明点が多い。本研究成果により,鉄過剰肝では化学物質に対する肝毒性の感受性が変質している可能性が示されたことから,慢性肝疾患患者の治療薬の選択時に肝鉄過剰の有無を考慮することで,より安全で効果的な治療法の選択につながることが期待される。また,肝鉄過剰を併発した非アルコール性脂肪性肝疾患(NAFLD)患者では脂質異常症や肝炎が増悪する可能性があることから,鉄代謝障害とマクロファージの活性化を標的としたNAFLDの新たな治療法の考案が期待される。

Report

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

    (14 results)

All 2023 2022 2021 2020

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] Absence of increased susceptibility to acetaminophen-induced liver injury in a diet induced NAFLD mouse model2023

    • Author(s)
      Izawa T, Travlos GS, Cortes RA, Clayton NP, Sills RC, Pandiri AR
    • Journal Title

      Toxicologic Pathology

      Volume: in press

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Dietary iron overload enhances Western diet induced hepatic inflammation and alters lipid metabolism in rats sharing similarity with human DIOS2022

    • Author(s)
      Fujiwara Sakura、Izawa Takeshi、Mori Mutsuki、Atarashi Machi、Yamate Jyoji、Kuwamura Mitsuru
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 21414-21414

    • DOI

      10.1038/s41598-022-25838-3

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analyses of hemorrhagic diathesis in high-iron diet-fed rats2021

    • Author(s)
      Inai Yohei、Izawa Takeshi、Mori Mutsuki、Atarashi Machi、Tsuchiya Seiichirou、Kuwamura Mitsuru、Yamate Jyoji
    • Journal Title

      Journal of Toxicologic Pathology

      Volume: 34 Issue: 1 Pages: 33-41

    • DOI

      10.1293/tox.2020-0004

    • NAID

      130007982457

    • ISSN
      0914-9198, 1881-915X
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dietary Iron Overload Differentially Modulates Chemically-Induced Liver Injury in Rats2020

    • Author(s)
      Mori Mutsuki、Izawa Takeshi、Inai Yohei、Fujiwara Sho、Aikawa Ryo、Kuwamura Mitsuru、Yamate Jyoji
    • Journal Title

      Nutrients

      Volume: 12 Issue: 9 Pages: 2784-2784

    • DOI

      10.3390/nu12092784

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Application of chimeric mouse with humanized liver in pathological research2023

    • Author(s)
      Izawa T
    • Organizer
      The 10th ASVP and 10th JCVP Joint Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ヒト成長ホルモン処置による脂肪肝抑制がヒト肝細胞キメラマウスの肝毒性感受性へ及ぼす影響の検討2022

    • Author(s)
      瓶井 知美,井澤 武史,高見 優生,田中 美有,桑村 充
    • Organizer
      第39回日本毒性病理学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] AI画像解析による肝毒性所見の定量化と血清ALT, ASTとの相関解析2022

    • Author(s)
      稲井 洋平,井澤 武史,瓶井 知美,田中 美有,山手 丈至,桑村 充
    • Organizer
      第39回日本毒性病理学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 鉄過剰による化合物誘発肝硬変の抑制に関わる転写因子 Nrf2の役割2022

    • Author(s)
      濱田 菜々子,井澤 武史,新 真智,瓶井 知美,藤原 奨,田中 美有,田口 恵子,山本 雅之,桑村 充
    • Organizer
      第165回日本獣医学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Influence of vitamin K on bleeding tendency in rats fed high-iron diets2022

    • Author(s)
      Inai Y, Izawa T, Fujiwara S, Tanaka M, Kuwamura M
    • Organizer
      The 38th Annual Meeting of the Japanese Society of Toxicologic Pathology and the 1st Meeting of the Asian Union of Toxicologic Pathology
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Influence of diabetes induction on rat NAFLD model2022

    • Author(s)
      Izawa T, Mizuguchi E, Yamate J, Kuwamura M
    • Organizer
      The 38th Annual Meeting of the Japanese Society of Toxicologic Pathology and the 1st Meeting of the Asian Union of Toxicologic Pathology
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 鉄過剰による薬物性肝障害の修飾に関わるオートファジーの解析2021

    • Author(s)
      藤原 奨,井澤 武史,相川 諒,桑村 充,山手 丈至
    • Organizer
      第164回日本獣医学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] ラット脂肪肝-肝腫瘍モデルにおける食餌性鉄過剰の病態修飾2021

    • Author(s)
      新 真智,井澤 武史,水口 恵理,桑村 充,山手 丈至
    • Organizer
      第37回日本毒性病理学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 鉄過剰による化合物誘発肝障害の軽減メカニズムの解明2020

    • Author(s)
      相川 諒,井澤 武史,森 睦貴,稲井 洋平,桑村 充,山手 丈至
    • Organizer
      第163回日本獣医学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] リポポリサッカライド投与を併用した代謝性肝疾患モデルの病態解析2020

    • Author(s)
      水口 恵理,井澤 武史,新 真智,桑村 充,山手 丈至
    • Organizer
      第163回日本獣医学会学術集会
    • Related Report
      2020 Research-status Report

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

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