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The role of HSP110 family, Apg-2 in NASH-related hepatic lipid and glucose metabolism.

Research Project

Project/Area Number 16K09368
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

YAMAGUCHI KANJI  京都府立医科大学, 医学(系)研究科(研究院), 助教 (50381950)

Research Collaborator Itoh Katsuhiko  京都大学, 医学研究科, 教授 (90281097)
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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords脂肪肝炎 / 分子シャペロン / LKB1 / HSP110 / Apg-2 / 脂肪肝 / ユビキチン化 / 肝癌 / 内科 / 蛋白質
Outline of Final Research Achievements

Hsp110 family, Apg-2 has a chaperone-like activity similar to Hsp70. However, the physiological and pathological functions of Apg-2 in NAFLD remain unclear. We studied HFD-induced liver steatosis in Apg-2-deficient mice for clarifying the role of Apg-2 in NAFLD. HFD for 12 weeks induced obesity and liver steatosis in wild-type mice but not in Apg-2-deficient mice. HFD-induced elevation of serum t-cholesterol and ALT levels were improved with enhanced phosphorylation levels of AMPKα in Apg-2-deficient mice. Hepatic mRNA levels of SREBP1c, FAS, and ACC were also significantly decreased compared with wild-type mice. Liver-specific overexpression of Apg-2 in Apg-2-deficient mice restored obesity and liver steatosis by decreasing phosphorylated AMPKα and promoting LKB1 ubiquitination and degradation. Hepatic Apg-2 expression promotes liver steatosis via AMPK signaling inhibition, suggesting that the regulation of Apg-2 activities is a therapeutic target for NAFLD.

Academic Significance and Societal Importance of the Research Achievements

分子シャペロンが細胞死を迎えるべき細胞を救済するだけでなく、脂質や糖代謝に影響することで慢性炎症や発癌を助長していると考えられた。本来、いかに栄養を貯蓄し、効率よく使用することが生存に重要であった細胞にとって、近年の過栄養状態は想定されない状況と考えられる。この中で、分子シャペロンApg-2がLKB1の分解を通じてエネルギー貯蓄に重要であるという本研究の結果は、脂肪肝炎の病態解明に新たな知見となり得る。HSP70とHSP110の脂肪肝炎における個々の役割を明らかにすることで、慢性肝炎から肝硬変、肝がんへ至る長期的な病期に応じた治療法の開発に繋がると考えられた。

Report

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

    (8 results)

All 2019 2018 2017 2016

All Presentation (6 results) (of which Int'l Joint Research: 2 results) Book (2 results)

  • [Presentation] The relationship between the PNPLA3, TLL1 polymorphism combination and advanced fibrosis in Japanese patients with non-alcoholic fatty liver disease.2019

    • Author(s)
      瀬古裕也、山口寛二、楳村敦詩、伊藤義人
    • Organizer
      EASL The International Liver Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 分子シャペロンAPG-2を標的にしたNAFLD治療戦略2018

    • Author(s)
      山口寛二, 石破博, 伊藤義人
    • Organizer
      第54回日本肝臓病学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 分子シャペロンApg-2をターゲットにした肝脂肪化治療戦略2017

    • Author(s)
      山口寛二、石破博、伊藤義人
    • Organizer
      第53回日本肝臓学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Apg-2 plays an important role in hepatic steatosis2017

    • Author(s)
      Yamaguchi Kanji, Ishiba Hiroshi, Seko Yuya, Umemura Atsushi, Itoh Yoshito
    • Organizer
      第1回ICFL The 1st International Conference on Fatty Liver
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Heat shock protein 110ファミリー・Apg-2の脂肪肝形成における役割2016

    • Author(s)
      山口寛二、石破 博、伊藤義人
    • Organizer
      第52回 日本肝臓学会総会
    • Place of Presentation
      幕張
    • Related Report
      2016 Research-status Report
  • [Presentation] Apg-2 is a key determinant of hepatic steatosis by regulating AMPK activity.2016

    • Author(s)
      Hiroshi Ishiba, Kanji Yamaguchi, Yoshito Itoh
    • Organizer
      The Liver Meeting 2016.
    • Place of Presentation
      Boston, USA
    • Related Report
      2016 Research-status Report
  • [Book] 肝胆膵 NASH/NAFLDの臨床の進歩と問題点 オベチコール酸(DSP-1747)によるNASH治療2018

    • Author(s)
      山口寛二, 瀬古裕也, 楳村敦詩, 西川太一朗, 森口理久, 伊藤義人
    • Total Pages
      7
    • Publisher
      アークメディア
    • Related Report
      2018 Annual Research Report
  • [Book] NASHにおける肝癌発生の実態2018

    • Author(s)
      伊藤義人, 山口寛二, 楳村敦詩, 森口理久, 原祐, 瀬古裕也
    • Total Pages
      7
    • Publisher
      臨床消化器内科
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2020-10-29  

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