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Clarification of pathogenesis of NASH(non-alcoholic steatohepatitis) using PDLIM2-deficient mice

Research Project

Project/Area Number 15K08536
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Immunology
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

TANAKA TAKASHI  国立研究開発法人理化学研究所, 統合生命医科学研究センター, チームリーダー (00415225)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords非アルコール性脂肪肝炎(NASH) / PDLIM2 / ユビキチンリガーゼ / 腸内細菌 / 脂質代謝 / 非アルコール性脂肪肝 / 非アルコール性脂肪肝炎
Outline of Final Research Achievements

NASH is a chronic hepatic inflammation associated with immune cell infiltration and fibrosis. We recently found that mice deficient in PDLIM2, a nuclear ubiquitin E3 ligase containing PDZ and LIM domains, spontaneously develop NASH-like pathology. Notably, PDLIM2-deficient mice develop NASH in the animal facility of Harvard University, but not in RIKEN facility. Since systemic inflammation can be modified by gut microbiota, we colonized gut microbiota of mice form Taconic Farms into germ-free PDLIM2-deficient mice, and found that PDLIM2-deficient mice with Taconic microbiota environment could develop NASH when we fed a normal chow or higher fat diet (9-15% fat). Microarray analysis of Kupffer cells in PDLIM2-deficient liver showed the upregulation inflammation and metabolism-related genes, which contribute to the NASH phenotype. These data suggest that Taconic microbiota or microbiota-derived metabolites are essential for the development of NASH in combination with PDLIM2-deficiency.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (13 results)

All 2017 2016 2015

All Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 2 results,  Acknowledgement Compliant: 2 results) Presentation (9 results) (of which Invited: 4 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses2017

    • Author(s)
      Shin C, Ito Y, Ichikawa S, Tokunaga M, Sakata-Sogawa K, Tanaka T
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 46097-46097

    • DOI

      10.1038/srep46097

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Clarification of the molecular mechanisms that negatively regulate inflammatory responses.2016

    • Author(s)
      Tanaka, T.
    • Journal Title

      Chronic Inflammation, Mechanisms and Regulation

      Volume: ー Pages: 109-118

    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Journal Article] PDLIM1 inhibits NF-κB-mediated inflammatory signaling by sequestering the p65 subunit of NF-κB in the cytoplasm.2015

    • Author(s)
      Ono, R., Kaisho, T., Tanaka, T.
    • Journal Title

      Scientific Reports

      Volume: 5 Issue: 1 Pages: 18327-18327

    • DOI

      10.1038/srep18327

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Microbiota-dependent development of non-alcoholic steatohepatitis (NASH) in PDLIM2-deficient mice.2017

    • Author(s)
      Tanaka T.
    • Organizer
      The 46th Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2017 Annual Research Report
  • [Presentation] Microbiota-dependent development of non-alcoholic steatohepatitis (NASH) in PDLIM2-deficient mice2017

    • Author(s)
      Tanaka T.
    • Organizer
      Luxembourg FNR-RIKEN Joint Symposium, Understanding Inflammatory Diseases beyond Complexity
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Molecular mechanism how Nahlsgen controls biological function of the skin2017

    • Author(s)
      Tanaka T.
    • Organizer
      NAHLS Research Symposium
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Negative regulation of inflammatory responses by LIM proteins2017

    • Author(s)
      Tanaka T.
    • Organizer
      The 1st RIKEN-McGill Symposium, Excellence in Immunology & Genetics
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] MKRN2 is a novel ubiquitin E3 ligase for p65 subunit of NF-κB, negatively regulating NF-κB-mediated inflammatory responses.2016

    • Author(s)
      Shin, C., Tanaka, T.
    • Organizer
      第45回日本免疫学会学術集会
    • Place of Presentation
      沖縄コンベンションセンター
    • Year and Date
      2016-12-07
    • Related Report
      2016 Research-status Report
  • [Presentation] The roles of LIM protein family in the regulation of inflammatory responses2016

    • Author(s)
      Tanaka, T.
    • Organizer
      第45回日本免疫学会学術集会
    • Place of Presentation
      沖縄コンベンションセンター
    • Year and Date
      2016-12-07
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] PDLIM1 negatively regulates NF-?B signaling by sequestrating p65 subunit of NF-κB in the cytoplasm in an IκBα-independent manner.2015

    • Author(s)
      Ono R, Tanaka T
    • Organizer
      第44回日本免疫学会学術集会
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2015-11-19
    • Related Report
      2015 Research-status Report
  • [Presentation] PDLIM7 promoted ubiquitin/proteasome-dependent degradation for p65 subunit of NF-κb through PDLIM2 protein stabilization.2015

    • Author(s)
      Sibazaki A, Tanaka T.
    • Organizer
      第44回日本免疫学会学術集会
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2015-11-19
    • Related Report
      2015 Research-status Report
  • [Presentation] Fbxo21, a component of ubiquitin E3 ligase complex, associates with PDLIM2 and specifically regulates NF-κB-mediated inflammatory signaling.2015

    • Author(s)
      Tanaka T, Shibazaki A, Ono R
    • Organizer
      第44回日本免疫学会学術集会
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Research-status Report
  • [Patent(Industrial Property Rights)] 創傷修復促進剤2017

    • Inventor(s)
      吉岡龍藏、田中陽子、矢口学、田中貴志
    • Industrial Property Rights Holder
      吉岡龍藏、田中陽子、矢口学、田中貴志
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-081239
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report

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Published: 2015-04-16   Modified: 2019-03-29  

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