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Elucidation of the association between non alcoholic steatohepatitis and endoplasmic reticulum stress by metabolomics of portal blood

Research Project

Project/Area Number 16K09336
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionTohoku University

Principal Investigator

KAKAZU EIJI  東北大学, 東北大学病院, 助教 (20509377)

Co-Investigator(Kenkyū-buntansha) 小暮 高之  東北大学, 医学系研究科, 非常勤講師 (70400330)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords遊離アミノ酸 / 非アルコール性脂肪性肝炎 / 非アルコール性脂肪性肝疾患 / NAFLD / 門脈血 / アミノ酸 / 脂肪肝 / 3D培養 / 潅流培養 / 肝細胞 / パルミチン酸 / オレイン酸 / 小胞体ストレス / 門脈
Outline of Final Research Achievements

The aim of this study is to elucidate the association between the imbalance of free amino acids (FAAs) in portal blood (PB) and the pathogenesis of hepatic steatosis in NAFLD. We measured metabolites in PB of fasting WT mice and NAFLD model mice. Then, we made two media that were consistent with the levels of FAAs in the PB of wt or NAFLD model mice. We found that the decrease of 7 FAAs, especially Met and Tyr, in the media induced TG accumulation and ER stress via the suppression of lipid secretion from hepatocytes. The high fat, L-methionine (Met) / L-tyrosine (Tyr) -deficient diet (HF-MTD) induced steatosis and ballooning pathologically in the liver of C57BL/6 mice, but the HF diet did not.

Academic Significance and Societal Importance of the Research Achievements

これまで非アルコール性脂肪性肝炎(NASH)の環境要因として過剰な糖質、脂質の関与は多くの研究で証明されてきたが、本研究で一部の遊離アミノ酸の不均衡も肝細胞脂肪変性を悪化させNASHの要因となる可能性が示唆された。また、本研究で開発した門脈血類似潅流培養は生体内の環境に近い培養法で、肝細胞の代謝研究を行う上で従来の培養法よりもはるかに優れていると考える。今後、更に研究を発展させることで候補アミノ酸の代謝を促進することでNASHの治療・予防につながる可能性がある。

Report

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

    (12 results)

All 2018 2017 2016

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (10 results) (of which Int'l Joint Research: 3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] The profiling of plasma free amino acids and the relationship between serum albumin and plasma-branched chain amino acids in chronic liver disease: a single-center retrospective study.2018

    • Author(s)
      Akitoshi Sano, Eiji Kakazu, Tatsuki Morosawa, Jun Inoue, Takayuki Kogure, Masashi Ninomiya, Tomoaki Iwata, Teruyuki Umetsu, Takuya Nakamura, Satoshi Takai, Tooru Shimosegawa
    • Journal Title

      Journal of Gastroenterology

      Volume: 印刷中 Issue: 8 Pages: 978-988

    • DOI

      10.1007/s00535-018-1435-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Decreased L-methionine / L-tyrosine in portal blood induces endoplasmic reticulum (ER) stress to hepatocytes via the suppression of lipid secretion in non-alcoholic fatty liver disease (NAFLD)2018

    • Author(s)
      Akitoshi Sano, Eiji Kakazu, Tatsuki Morosawa, Jun Inoue, Masashi Ninomiya, Tomoaki Iwata, Satoshi Takai, Takuya Nakamura, Tooru Shimosegawa, Atsushi Masamune
    • Organizer
      アメリカ肝臓学会年次集会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 門脈血類似灌流培養による肝細胞脂肪変性に関与する遊離アミノ酸の検討2018

    • Author(s)
      佐野晃俊、嘉数英二、井上淳、二宮匡史、岩田朋晃、 梅津輝行、高井智、中村琢也、正宗淳、下瀬川徹
    • Organizer
      第54回 日本肝臓学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The relationship between serum albumin and plasma-branched chain amino acids (pBCAAs) in recent chronic liver disease: a single-center retrospective study.2018

    • Author(s)
      Eiji Kakazu, Akitoshi Sano, Tatsuki Morosawa, Jun Inoue, Masashi Ninomiya, Tomoaki Iwata, Satoshi Takai, Takuya Nakamura, Tooru Shimosegawa, Atsushi Masamune
    • Organizer
      FALK symposium 212
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 各種慢性肝疾患の肝予備能と血漿遊離アミノ酸プロファイル2018

    • Author(s)
      嘉数英二 佐野晃俊 諸沢樹 井上淳 二宮匡史 岩田朋晃 梅津輝行 高井智 中村琢也 正宗 淳下瀬川徹
    • Organizer
      第104回 消化器病学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The relationship between the plasma free amino acids and the pathological features in nonalcoholic fatty liver disease (NAFLD).2017

    • Author(s)
      Eiji Kakazu, Akitoshi Sano, Tatsuki Morosawa, Jun Inoue, Takayuki Kogure, Masashi Ninomiya, Tomoaki Iwata, Teruyuki Umetsu, Takuya Nakamura, Satoshi Takai, Tooru Shimosegawa
    • Organizer
      アメリカ肝臓学会 annual meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 門脈血類似・三次元潅流培養による肝細胞に対する脂肪毒性と小胞体ストレスの評価2017

    • Author(s)
      嘉数英二、佐野晃俊、井上 淳、小暮高之、二宮匡史、諸沢 樹、梅津輝行、高井 智、中村琢也、岩田朋晃、下瀬川徹
    • Organizer
      肝臓学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 末梢血中遊離アミノ酸を用いた非アルコール性脂肪性肝疾患・肝炎(NAFLD / NASH)の線維化予測式の検討2016

    • Author(s)
      嘉数英二、諸沢樹、下瀬川徹
    • Organizer
      第41回日本肝臓学会東部会
    • Place of Presentation
      京王プラザホテル(新宿区 東京)
    • Year and Date
      2016-12-08
    • Related Report
      2016 Research-status Report
  • [Presentation] The evaluation of endoplasmic reticulum (ER) stress in hepatocytes under a new 3D perfusion culture system consistent with hepatic portal blood.2016

    • Author(s)
      Eiji Kakazu, Jun Inoue, Takayuki Kogure, Masashi Ninomiya, Tatsuki Morosawa, Teruyuki Umetsu, Takuya Nakamura, Satoshi Takai, Tooru Shimosegawa
    • Organizer
      American Association for the Study of Liver Diseases
    • Place of Presentation
      John B. Hynes Veterans Memorial Convention Center(ボストン 米国)
    • Year and Date
      2016-11-13
    • Related Report
      2016 Research-status Report
  • [Presentation] Profiling of hepatic portal blood metabolites in Non-alcoholic fatty liver disease mice by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)2016

    • Author(s)
      Eiji Kakazu, Harmeet Malhi, Jun Inoue, Masashi Ninomiya, Takayuki Kogure, Tooru Shimosegawa
    • Organizer
      Asian Pacific Digestive Week
    • Place of Presentation
      神戸コンベンションセンター(兵庫県神戸市)
    • Year and Date
      2016-10-04
    • Related Report
      2016 Research-status Report
  • [Presentation] 非アルコール性脂肪酸肝炎においてパルミチン酸はIRE1a / XBP1 依存性に肝細胞から細胞外顆粒を放出させ、マクロファージを集積させる2016

    • Author(s)
      嘉数英二、Harmeet malhi、下瀬川徹
    • Organizer
      第52回日本肝臓学会総会
    • Place of Presentation
      ホテルニューオータニ幕張(千葉県千葉市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] 肝脂肪低減剤2018

    • Inventor(s)
      嘉数英二
    • Industrial Property Rights Holder
      嘉数英二
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2017 Research-status Report

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

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