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Roles of inflammation- and stress-related signaling pathways in NASH-associated hepatocarcinogenesis

Research Project

Project/Area Number 25893042
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

HAYATO NAKAGAWA  東京大学, 医学部附属病院, 助教 (00555609)

Project Period (FY) 2013-08-30 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords非アルコール性脂肪肝炎 / 肝細胞癌 / NASH / 肝癌 / ERストレス / 炎症
Outline of Final Research Achievements

This study analyzed the mechanisms of NASH- and obesity-associated hepatocarcinogenesis using new mouse models. Feeding an HFD to MUP-uPA mice resulted in steatohepatitis that closely resembles the pathology of human NASH, eventually leading to spontaneous development of HCC. In this mouse model, the vicious cycle of ER stress and hypernutrition synergistically aggravates lipid accumulation in the liver via SREBP activation, which leads to excess oxidative stress, ballooning degeneration, and susceptibility to lipotoxic cell death. In parallel, increased TNFα expression during this process further accelerates NASH and HCC development in a TNF receptor 1-IKK-NF-κB-dependent manner. Reducing ER stress using chemical chaperones significantly improved liver pathology, suggesting that interrupting this vicious cycle might be a promising therapeutic target for NASH and HCC.

Report

(3 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • Research Products

    (5 results)

All 2015 2014 Other

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 1 results) Presentation (2 results)

  • [Journal Article] Impact of serum levels of interleukin-6 and adiponectin on all-cause, liver-related, and liver-unrelated mortality in chronic hepatitis C patients2015

    • Author(s)
      Nakagawa H, Fujiwara N, Tateishi R, Arano T, Nakagomi R, Kondo M, Minami T, Sato M, Uchino K, Enooku K, Asaoka Y, Kondo Y, Shiina S, Yoshida H, Koike K.
    • Journal Title

      J Gastroenterol Hepatol.

      Volume: 30 Issue: 2 Pages: 379

    • DOI

      10.1111/jgh.12719

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development2014

    • Author(s)
      Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, Zhong Z, Valasek MA, Seki E, Hidalgo J, Koike K, Kaufman RJ, Karin M.
    • Journal Title

      Cancer Cell

      Volume: 26 Issue: 3 Pages: 331-343

    • DOI

      10.1016/j.ccr.2014.07.001

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis.2014

    • Author(s)
      Nakagawa H, Hikiba Y, Hirata Y, Font-Burgada J, Sakamoto K, Hayakawa Y, Taniguchi K, Umemura A, Kinoshita H, Sakitani K, Nishikawa Y, Hirano K, Ikenoue T, Ijichi H, Dhar D, Shibata W, Akanuma M, Koike K, Karin M, Maeda S.
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 111 Issue: 3 Pages: 1090-1095

    • DOI

      10.1073/pnas.1322731111

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] 新規マウスモデルを用いたNASH発癌機構の解明2014

    • Author(s)
      中川勇人、小池和彦
    • Organizer
      肝臓と糖尿病・代謝研究会
    • Place of Presentation
      東京
    • Year and Date
      2014-07-04
    • Related Report
      2014 Annual Research Report
  • [Presentation] 新規マウスモデルを用いたNASH肝癌におけるTNFαの役割解析

    • Author(s)
      中川勇人、小池和彦
    • Organizer
      JDDW2013
    • Place of Presentation
      グランドプリンスホテル新高輪
    • Related Report
      2013 Annual Research Report

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Published: 2013-09-12   Modified: 2019-07-29  

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