Investigation of the regulatory mechanism of hepatic glucose response

• Project/Area Number: 22K19545
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Kanazawa 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: ¥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。

Research Products

• [Int'l Joint Research] 南デンマーク大学(デンマーク)
• [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
  • 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 Microscopy (2024)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models (2023)
  • 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
  • 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
  • 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 mice (2023)
  • 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
  • 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
  • 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
  • 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
  • Invited
• [Presentation] Modal shift of hepatocyte death in nonalcoholic fatty liver disease (2022)
  • Author(s): 井上啓
  • Organizer: 第65回日本糖尿病学会年次学術集会
  • 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
• [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/