• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular mechanism of hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis

Research Project

Project/Area Number 16K08732
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

ITOH Michiko  東京医科歯科大学, 大学院医歯学総合研究科, ジョイントリサーチ講座准教授 (00581860)

Research Collaborator SUGANAMI takayoshi  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords慢性炎症 / マクロファージ / crown-like structure / 細胞死 / NASH / 線維芽細胞
Outline of Final Research Achievements

We have reported a histological structure, termed hepatic crown-like structure (hCLS), in which CD11c-positive macrophages surround dead hepatocytes, a prominent feature of NASH using murine model of non-alcoholic steatohepatitis. In this study, we demonstrated that hCLS-constituting macrophages could be a novel macrophage subset that drives hepatocyte death-triggered liver fibrosis. We also showed that resident macrophages are a major cellular source of CD11c-positive macrophages constituting hCLS, which exhibited gene expression profiles distinct from CD11c-negative macrophages scattered in the liver. Moreover, depletion of CD11c-positive macrophages abolished hCLS formation and fibrogenesis in NASH. This study sheds light on the role of resident macrophages, in addition to recruited macrophages, in the pathogenesis of NASH.

Academic Significance and Societal Importance of the Research Achievements

慢性炎症を基盤とする様々な生活習慣病の病態形成においてマクロファージが重要な役割を果たすことが知られているが、マクロファージは非常に多様性の高い細胞集団であり、最近では病態形成に直接的な役割を果たす「疾患特異的マクロファージ」と理解が求められている。NASHの肝臓におけるCD11c陽性マクロファージは病理学的構造に基づく疾患特異的マクロファージと考えられ、その活性化機構および病態生理的意義の解明により、新規バイオマーカーや治療標的の開発に繋がることが期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (18 results)

All 2018 2017 2016 Other

All Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (11 results) (of which Int'l Joint Research: 1 results,  Invited: 3 results) Remarks (2 results)

  • [Journal Article] Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis.2018

    • Author(s)
      T. Goto, M. Itoh, T. Suganami, S. Kanai, I. Shirakawa, T. Sakai, M. Asakawa,T. Yoneyama, T. Kai, Y. Ogawa.
    • Journal Title

      Sci. Rep.

      Volume: 8 Issue: 1 Pages: 8157-8157

    • DOI

      10.1038/s41598-018-26383-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH2018

    • Author(s)
      Shiba Kumiko、Tsuchiya Kyoichiro、Komiya Chikara、Miyachi Yasutaka、Mori Kentaro、Shimazu Noriko、Yamaguchi Shinobu、Ogasawara Naomi、Katoh Makoto、Itoh Michiko、Suganami Takayoshi、Ogawa Yoshihiro
    • Journal Title

      Sci. Rep.

      Volume: 8 Issue: 1 Pages: 2362-2362

    • DOI

      10.1038/s41598-018-19658-7

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors2018

    • Author(s)
      Chiyonobu Norimichi、Shimada Shu、Akiyama Yoshimitsu、Mogushi Kaoru、Itoh Michiko、Akahoshi Keiichi、Matsumura Satoshi、Ogawa Kosuke、Ono Hiroaki、Mitsunori Yusuke、Ban Daisuke、Kudo Atsushi、Arii Shigeki、Suganami Takayoshi、Yamaoka Shoji、Ogawa Yoshihiro、Tanabe Minoru、Tanaka Shinji
    • Journal Title

      Am. J. Pathol.

      Volume: 188 Issue: 5 Pages: 1213-1224

    • DOI

      10.1016/j.ajpath.2018.01.012

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis2017

    • Author(s)
      Itoh Michiko、Suganami Takayoshi、Kato Hideaki、Kanai Sayaka、Shirakawa Ibuki、Sakai Takeru、Goto Toshihiro、Asakawa Masahiro、Hidaka Isao、Sakugawa Hiroshi、Ohnishi Koji、Komohara Yoshihiro、Asano Kenichi、Sakaida Isao、Tanaka Masato、Ogawa Yoshihiro
    • Journal Title

      JCI Insight

      Volume: 2 Issue: 22 Pages: 1-16

    • DOI

      10.1172/jci.insight.92902

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis.2017

    • Author(s)
      C. Komiya, M. Tanaka, K. Tsuchiya, N. Shimazu, K. Mori, S. Furuke, Y. Miyachi, K. Shiba, S. Yamaguchi, K. Ikeda, K. Ochi, K. Nakabayashi, K. Hata, M. Itoh, T. Suganami, Y. Ogawa.
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 44754-44754

    • DOI

      10.1038/srep44754

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] NASH発症に重要なマクロファージサブセットの同定2018

    • Author(s)
      伊藤美智子、菅波孝祥、加藤秀昭、金井紗綾香、白川伊吹、酒井建、後藤俊宏、浅川雅博、小川佳宏
    • Organizer
      第91回日本内分泌学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 死細胞とマクロファージの相互作用に注目したNASH発症機構の解2018

    • Author(s)
      伊藤美智子、菅波孝祥、加藤秀昭、金井紗綾香、白川伊吹、酒井建、後藤俊宏、浅川雅博、小川佳宏
    • Organizer
      第61回日本糖尿病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 死細胞を起点とするNASH発症機構の解明 ー新規マウスモデルの確立を通してー2018

    • Author(s)
      伊藤美智子、菅波孝祥、小川佳宏
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] CD11c-positive macrophages drive obesity-induced liver fibrosis in a murine model of NASH2018

    • Author(s)
      Michiko Itoh
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 細胞死を起点とする非アルコール性脂肪性肝炎発症機構の解明2017

    • Author(s)
      伊藤美智子、菅波孝祥、金井紗綾香、白川伊吹、小川佳宏
    • Organizer
      第31回日本糖尿病・肥満動物学会
    • Place of Presentation
      はまぎんホールヴィアマーレ(神奈川県横浜市)
    • Year and Date
      2017-02-10
    • Related Report
      2016 Research-status Report
  • [Presentation] 細胞死を起点とするマクロファージの形質変化と非アルコール性脂肪性肝炎2017

    • Author(s)
      伊藤美智子、菅波孝祥、金井紗綾香、白川伊吹、小川佳宏
    • Organizer
      第54回日本臨床分子医学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 非アルコール性脂肪性肝炎の病態形成におけるhepatic crown-like structureの病態生理的意義2017

    • Author(s)
      伊藤美智子、菅波孝祥、金井紗綾香、白川伊吹、小川佳宏
    • Organizer
      第90回日本内分泌学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] NASH発症過程におけるマクロファージの形質変化-hepatic crown-like structureに注目して-2017

    • Author(s)
      伊藤美智子、菅波孝祥、金井紗綾香、白川伊吹、酒井健、後藤俊宏、浅川雅博、日高勲、坂井田功、小川佳宏
    • Organizer
      第38回日本肥満学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Hepatocyte death-triggered CD11c-positive macrophage accumulation induces liver fibrosis in a murine model of non-alcoholic steatohepatitis.2017

    • Author(s)
      Michiko Itoh, Takayoshi Suganami, Sayaka Kanai, Ibuki Shirakawa, Takeru Sakai, Toshihiro Goto, Masahiro Asakawa, Isao Hidaka, Isao Sakaida, Yoshihiro Ogawa
    • Organizer
      AASLD The Liver Meeting 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 新しいマウスモデルを用いたNASH発症機構の解明と医学応用2016

    • Author(s)
      伊藤美智子、菅波孝祥、小川佳宏
    • Organizer
      第37回日本肥満学会
    • Place of Presentation
      東京ファッションタウンビル(東京都江東区)
    • Year and Date
      2016-10-07
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 非アルコール性脂肪性肝炎の病態形成におけるhepatic crown-like structureの病態生理的意義2016

    • Author(s)
      伊藤美智子、菅波孝祥、小川佳宏
    • Organizer
      第37回日本炎症・再生医学会
    • Place of Presentation
      京都市勧業館みやこめっせ(京都府京都市)
    • Year and Date
      2016-06-16
    • Related Report
      2016 Research-status Report
  • [Remarks] 東京医科歯科大学大学院医歯学総合研究科 分子内分泌代謝学分野

    • URL

      http://www.tmd.ac.jp/grad/cme/

    • Related Report
      2017 Research-status Report
  • [Remarks] 東京医科歯科大学大学院医歯学総合研究科 分子内分泌代謝学分野

    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi