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The role of macrophages in the progression of fibrosis of NASH and its regulation by nutritional factors

Research Project

Project/Area Number 20K19676
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 59040:Nutrition science and health science-related
Research InstitutionThe University of Tokushima

Principal Investigator

SHIMIZU Mayuko  徳島大学, 大学院医歯薬学研究部(医学域), 講師 (20759021)

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: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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)
KeywordsNASH / 線維化 / 可視化 / リン脂質 / 病態特異的マクロファージ / ベルベリン / コレステロール / コール酸 / 非アルコール性脂肪肝炎 / 肝線維化 / マクロファージ / マウス / 肝線維化モデルマウス / A/Jマウス / モデル動物 / 病的脂質 / 肝線維化モデル動物 / TSNOマウス / 脂質
Outline of Research at the Start

非アルコール性脂肪肝炎(NASH)は肝臓で炎症が持続して線維化を生じ、肝硬変や肝癌などに至る可能性がある疾患である。線維化は進行するほど治療が困難となるため肝線維化治療が不可欠である。線維化を促進する物質を分泌するマクロファージはその治療標的となると考えられる。その一方で、生活習慣病であるNASHの根本的な原因、すなわち栄養因子などを是正しない限り、治療薬で線維化進行を抑えられたとしても再発するリスクがある。
本研究ではマクロファージが活性化して肝炎から線維化に至る機構を栄養因子の観点から解明し、栄養因子によってマクロファージを制御することで肝線維化の進展および再発予防法を確立する。

Outline of Final Research Achievements

This study hypothesized that macrophage control inhibits the progression to fibrosis in non-alcoholic steatohepatitis. In a novel animal model of NASH fibrosis (iHFC-A/J mice), macrophage recruitment to the liver was increased with disease progression. After phagocytosed lipids, aggregated and activated, macrophages interacted with the surrounding fibroblasts, resulting in fibrosis progression, which was visualized histologically in the mouse model. Using this model, it was possible to evaluate that berberine suppresses macrophage aggregation and fibrogenesis. Because I demonstrated that berberine did not promote hepatic lipid efflux,it was suggested that berberine may directly regulate macrophages. This study indicated the usefulness of macrophage regulation in suppressing the onset of fibrosis in NASH.

Academic Significance and Societal Importance of the Research Achievements

ステージ2以上の高度な線維化には肝線維化特効薬による処置がまず必要ではあるものの、生活習慣に端を発するNASHのような疾患は原因を取り除かない限り同様の病態が再発する可能性は高い。本研究はマクロファージ不活化を介した治療法の開発でなく、マクロファージを活性化する特定の脂質を明らかにし、NASH線維化の予防あるいは再発防止につなげ、最終的に肝線維化の根治を目指すためのエビデンスになると考えられる。

Report

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

    (19 results)

All 2023 2022 2021 2020

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (10 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Inhibitory effect of non-alcoholic steatohepatitis on colon cancer liver metastasis.2023

    • Author(s)
      Yamada S, Morine Y, Ikemoto T, Saito Y, Miyazaki K, Shimizu M, Tsuneyama K, Shimada M.
    • Journal Title

      European Journal of Surgical Oncology

      Volume: 49 Issue: 2 Pages: 410-415

    • DOI

      10.1016/j.ejso.2022.11.002

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of Vancomycin Treatment and Gut Microbiota on Bile Acid Metabolism and the Development of Non-Alcoholic Steatohepatitis in Mice2023

    • Author(s)
      Kasai Kaichi、Igarashi Naoya、Tada Yuki、Kani Koudai、Takano Shun、Yanagibashi Tsutomu、Usui-Kawanishi Fumitake、Fujisaka Shiho、Watanabe Shiro、Ichimura-Shimizu Mayuko、Takatsu Kiyoshi、Tobe Kazuyuki、Tsuneyama Koichi、Furusawa Yukihiro、Nagai Yoshinori
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 4 Pages: 4050-4050

    • DOI

      10.3390/ijms24044050

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Influence of Fasting Time on Serum and Hepatic Lipid Profiles in a Sprague-Dawley Rat Model of Nonalcoholic Steatohepatitis2022

    • Author(s)
      OMAGARI Katsuhisa、UCHIDA Miku、TAGAWA Yumeno、YOGO Mizuki、INAGAKI Kae、HONGO Ryoko、TAKEUCHI Shouhei、SURUGA Kazuhito、KOBA Kazunori、ICHIMURA-SHIMIZU Mayuko、TSUNEYAMA Koichi
    • Journal Title

      Journal of Nutritional Science and Vitaminology

      Volume: 68 Issue: 5 Pages: 409-419

    • DOI

      10.3177/jnsv.68.409

    • ISSN
      0301-4800, 1881-7742
    • Year and Date
      2022-10-31
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dietary Cholic Acid Exacerbates Liver Fibrosis in NASH Model of Sprague Dawley Rats Fed a High-Fat and High-Cholesterol Diet2022

    • Author(s)
      Ichimura-Shimizu Mayuko、Watanabe Shiro、Kashirajima Yuka、Nagatomo Ami、Wada Hitomi、Tsuneyama Koichi、Omagari Katsuhisa
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 16 Pages: 9268-9268

    • DOI

      10.3390/ijms23169268

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice2022

    • Author(s)
      Shao Wenhua、Jargalsaikhan Orgil、Ichimura-Shimizu Mayuko、Cai Qinyi、Ogawa Hirohisa、Miyakami Yuko、Atsumi Kengo、Tomita Mitsuru、Sutoh Mitsuko、Toyohara Shunji、Hokao Ryoji、Kudo Yasusei、Oya Takeshi、Tsuneyama Koichi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 19 Pages: 11923-11923

    • DOI

      10.3390/ijms231911923

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel mouse model of non-alcoholic steatohepatitis suggests that liver fibrosis initiates around lipid-laden macrophages2022

    • Author(s)
      Mayuko Ichimura-Shimizu, Yosuke Tsuchiyama, Yuki Morimoto, Minoru Matsumoto, Tomoko Kobayashi, Satoshi Sumida, Takumi Kakimoto, Takeshi Oya, Hirohisa Ogawa, Michiko Yamashita, Satoru Matsuda, Katsuhisa Omagari, Shu Taira, Koichi Tsuneyama
    • Journal Title

      The American Journal of Pathology

      Volume: 192 Issue: 1 Pages: 31-42

    • DOI

      10.1016/j.ajpath.2021.10.002

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Verification of the Impact of Blood Glucose Level on Liver Carcinogenesis and the Efficacy of a Dietary Intervention in a Spontaneous Metabolic Syndrome Model2021

    • Author(s)
      Mayuko Ichimura-Shimizu, Takeshi Kageyama, Takeshi Oya, Hirohisa Ogawa, Minoru Matsumoto, Satoshi Sumida, Takumi Kakimoto, Yuko Miyakami, Ryosuke Nagatomo, Koichi Inoue, Chunmei Cheng and Koichi Tsuneyama
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 23 Pages: 12844-12844

    • DOI

      10.3390/ijms222312844

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 非アルコール性脂肪肝炎および脳機能障害における脂質の挙動2021

    • Author(s)
      清水 真祐子
    • Journal Title

      アグリバイオ

      Volume: 5 Pages: 521-525

    • Related Report
      2021 Research-status Report
  • [Journal Article] Development of a novel mouse model of diet-induced nonalcoholic steatohepatitis-related progressive bridging fibrosis2020

    • Author(s)
      Ichimura-Shimizu Mayuko、Omagari Katsuhisa、Yamashita Michiko、Tsuneyama Koichi
    • Journal Title

      Bioscience, Biotechnology, and Biochemistry

      Volume: 85 Issue: 4 Pages: 941-947

    • DOI

      10.1093/bbb/zbaa107

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 非アルコール性脂肪性肝疾患モデルマウスの肝臓に蓄積した脂肪滴の相転移2023

    • Author(s)
      安丸 和樹, 長谷 栄治, 清水 真祐子, 安井 武史, 常山 幸一, 南川 丈夫
    • Organizer
      第70回応用物理学会春季学術講演会
    • Related Report
      2022 Annual Research Report
  • [Presentation] NASHモデルマウスにおけるベルベリンによる肝線維化抑制効果の検討2022

    • Author(s)
      中原穂乃佳,渡部あすか,清水真祐子,小川博久,常山幸一
    • Organizer
      第111回日本病理学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] リソソーム酸性リパーゼ欠損症および高脂肪・コレステロール・コール酸食誘導NASHモデルマウスの病理所見の近似性2022

    • Author(s)
      清水真祐子、常山幸一
    • Organizer
      第58回肝臓学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Accumulation of α-synuclein in hepatocytes in NASH liver and usefulness in pathological diagnosis2022

    • Author(s)
      Takumi Kakimoto, Mayuko Shimizu, Hirohisa Ogawa, Minoru Matsumoto, Takeshi Oya, Masato Hosokawa, Koichi Tsuneyama
    • Organizer
      Digestive Disease Week
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 非アルコール性脂肪性肝疾患モデルマウスの肝臓に蓄積した脂肪滴のラマン・SHGイメージング2022

    • Author(s)
      安丸 和樹, 南川 丈夫, 長谷 栄治, 清水 真祐子, 安井 武史, 常山 幸一
    • Organizer
      Optics and Photonics Japan 2022
    • Related Report
      2022 Annual Research Report
  • [Presentation] 非アルコール性脂肪肝炎病態のリン脂質イメージング:病態形成における脳肝相関の可能性探索2021

    • Author(s)
      清水 真祐子, 平 修, 小川 博久, 常山 幸一
    • Organizer
      第69回質量分析総合討論会2021
    • Related Report
      2021 Research-status Report
  • [Presentation] NASH線維化の連続的数値による定量的評価のための新規画像解析法の開発2021

    • Author(s)
      清水 真祐子, 富永 俊弼, 筒井 朱美
    • Organizer
      第57回日本肝臓学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] イメージング質量分析によるNASH線維化肝で増加する脂質の同定2020

    • Author(s)
      清水真祐子、平修、松本穣 、尾矢剛志 、 小川博久 、常山幸一
    • Organizer
      日本病理学会第109回総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 実験的モデル動物作成に用いられる高脂肪・コレステロール食に含まれるコール酸のNASH病態形成への影響2020

    • Author(s)
      清水真祐子、大曲勝久、常山幸一
    • Organizer
      第56回日本肝臓学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] A novel image analysis technology that can verify quantification and progress pattern of NASH fibrosis2020

    • Author(s)
      Mayuko Shimizu, Shunsuke Tominaga, Koichi Tsuneyama
    • Organizer
      Liver meeting (AASLD)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research

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

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