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Investigation of the regulatory mechanism of hepatic glucose response

Research Project

Project/Area Number 22K19545
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
Research InstitutionKanazawa University

Principal Investigator

Inoue Hiroshi  金沢大学, 新学術創成研究機構, 教授 (50397832)

Project Period (FY) 2022-06-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2023: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2022: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Keywords肝臓 / 糖取り込み
Outline of Research at the Start

本研究の目的は、肝グルコース取り込みに伴う遺伝子転写制御とその破綻の解明である。肝グルコース取り込みは、脂肪合成酵素やヘパトカインなどの遺伝子転写を介して、肝臓糖脂質代謝を制御する。また、肥満・インスリン抵抗性では、肝グルコース取り込みに伴う肝臓遺伝子転写制御も障害される。本研究において、肝グルコース取り込み制御メカニズムとグルコース応答性遺伝子転写とのシステム連関について、肝グルコース取り込み制御分子の変異マウスを用いて解明する。

Outline of Final Research Achievements

The liver takes up glucose and triggers glucose responses, including not only hepatic metabolism but also transcriptional regulation and inter-organ crosstalk with other organs. In overnutrition and obesity, hepatic glucose response is impaired, which contributes to the pathogenesis of glucose intolerance, insulin resistance, and fatty liver. This study aimed to elucidate the role of glucokinase regulatory protein (GKRP) in the control mechanism of hepatic glucose response. GKRP undergoes increased acetylation at lysine 126 (K126) due to overnutrition and obesity. Although K126R mutant knock-in mice of GKRP did not show significant changes in hepatic glucose metabolism, transcriptome analysis revealed changes in gene expression. This suggests that GKRP may be a novel glucose response control molecule.

Academic Significance and Societal Importance of the Research Achievements

肝グルコース応答障害は、耐糖能障害からインスリン抵抗性・脂肪肝などの様々な生活習慣病の病因となる。肝グルコース応答の制御分子としてGckが知られてきたが、Gckを標的とした生活習慣病治療薬の開発は十分な成果が得られていない。本研究において、新規な肝グルコース応答のメカニズム分子候補としてGKRPを見出すことは、生活習慣病の新規治療標的の解明に繋がる。さらに、生活習慣病の発症と増悪において、肝グルコース応答とその障害が果たす役割の解明へと繋がる。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (12 results)

All 2024 2023 2022 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (3 results) (of which Invited: 3 results) Remarks (2 results)

  • [Int'l Joint Research] 南デンマーク大学(デンマーク)

    • Related Report
      2022 Research-status Report
  • [Journal Article] Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity.2024

    • Author(s)
      Bai Y, Morita K, Kokaji T, Hatano A, Ohno S, Egami R, Pan Y, Li D, Yugi K, Uematsu S, Inoue H, Inaba Y, Suzuki Y, Matsumoto M, Takahashi M, Izumi Y, Bamba T, Hirayama A, Soga T, Kuroda S*.
    • Journal Title

      iScience

      Volume: 27(3) Issue: 3 Pages: 109121-109121

    • DOI

      10.1016/j.isci.2024.109121

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An Efficient Method for Isolating and Purifying Nuclei from Mice Brain for Single-Molecule Imaging Using High-Speed Atomic Force Microscopy2024

    • Author(s)
      Qiu Yujia、Sajidah Elma Sakinatus、Kondo Sota、Narimatsu Shinnosuke、Sandira Muhammad Isman、Higashiguchi Yoshiki、Nishide Goro、Taoka Azuma、Hazawa Masaharu、Inaba Yuka、Inoue Hiroshiら
    • Journal Title

      Cells

      Volume: 13 Issue: 3 Pages: 279-279

    • DOI

      10.3390/cells13030279

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models2023

    • Author(s)
      Matsukawa Toshiya、Yagi Takashi、Uchida Tohru、Sakai Mashito、Mitsushima Masaru、Naganuma Takao、Yano Hiroyuki、Inaba Yuka、Inoue Hiroshi、Yanagida Keisuke、Uematsu Masaaki、Nakao Kazuki、Nakao Harumi、Aiba Atsu、Nagashima Yoji、Kubota Tetsuya、Kubota Naoto
    • Journal Title

      JCI Insight

      Volume: 8 Issue: 17

    • DOI

      10.1172/jci.insight.161282

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] L-type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis.2023

    • Author(s)
      Park G, Fukasawa K, Horie T, Masuo Y, Inaba Y, Tatsuno T, Yamada T, Tokumura K, Iwahashi S, Iezaki T, Kaneda K, Kato Y, Ishigaki Y, Mieda M, Tanaka T, Ogawa K, Ochi H, Sato S, Shi YB, Inoue H, Lee H, Hinoi E.
    • Journal Title

      JCI Insight

      Volume: 8 Issue: 7

    • DOI

      10.1172/jci.insight.154925

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice2023

    • Author(s)
      Inaba Yuka、Hashiuchi Emi、Watanabe Hitoshi、Kimura Kumi、Oshima Yu、Tsuchiya Kohsuke et al.
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 167-167

    • DOI

      10.1038/s41467-023-35804-w

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states.2022

    • Author(s)
      Kokaji T, Eto M, Hatano A, Yugi K, Morita K, Ohno S, Fujii M, Hironaka KI, Ito Y, Egami R, Uematsu S, Terakawa A, Pan Y, Maehara H, Li D, Bai Y, Tsuchiya T, Ozaki H, Inoue H, Kubota H, Suzuki Y, Hirayama A, Soga T, Kuroda S.
    • Journal Title

      Sci Rep

      Volume: 12 Issue: 1 Pages: 13719-13719

    • DOI

      10.1038/s41598-022-17964-9

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 迷走神経による膵内分泌制御とその障害2023

    • Author(s)
      井上啓
    • Organizer
      第66回日本糖尿病学会年次学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 迷走神経性臓器連関による糖代謝恒常性維持とその破綻2022

    • Author(s)
      井上啓
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] Modal shift of hepatocyte death in nonalcoholic fatty liver disease2022

    • Author(s)
      井上啓
    • Organizer
      第65回日本糖尿病学会年次学術集会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Remarks] 金沢大学新学術創成研究機構栄養・代謝研究ユニット

    • URL

      https://inoue.w3.kanazawa-u.ac.jp/index.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 金沢大学新学術創成研究機構栄養・代謝研究ユニット

    • URL

      https://inoue.w3.kanazawa-u.ac.jp/

    • Related Report
      2022 Research-status Report

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Published: 2022-07-05   Modified: 2025-01-30  

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