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Understanding the role of disorder of vagus function in lifestyle-related diseases

Research Project

Project/Area Number 18KT0020
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund
Section特設分野
Research Field Complex Systems Disease Theory
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) 2018-07-18 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywords生活習慣病 / 迷走神経 / 肝臓 / 臓器連関
Outline of Final Research Achievements

Nonalcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, confers high risk of liver fibrosis and chronic liver injury. In this study, using systemic α7 nicotinic acetylcholine receptor (A7nAchR) knockout mice (A7KO), we investigated the role of A7nAchR in NASH. Specifically, A7KO mice were fed an atherogenic high-fat diet (AD), which induce NASH. Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in AD mice, and we found the plasma transaminase level increase was higher in A7KO mice than in control mice. A7KO mice fed an AD showed significant upregulation of fibrosis-related genes and proinflammatory-cytokine genes in the liver. Histological analysis with Sirius red revealed that AD exacerbated liver fibrosis in A7KO mice. From these findings, it is clear that A7nAchR deficiency exacerbates hepatitis and fibrosis due to hepatic fat accumulation.

Academic Significance and Societal Importance of the Research Achievements

本研究からα7型ニコチン受容体(A7nAchR)が、非アルコール性脂肪肝炎(NASH)の新規な予防・治療薬候補であることを見出した。しかし、A7nAchRは中枢神経作用に多く発現しており、A7nAchRアゴニストの中枢神経作用はNASH治療薬としての妨げとなる可能性がある。NASH予防・治療へのA7nAchR活性化の応用には、肝臓以外の臓器におけるA7nAchR作用の更なる解析と、アゴニストの肝臓特異的なドラッグデリバリー法の開発が必要であると考えられた。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (28 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (13 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 12 results,  Open Access: 11 results) Presentation (10 results) (of which Int'l Joint Research: 4 results,  Invited: 8 results) Remarks (3 results)

  • [Int'l Joint Research] University of Southern Denmark(デンマーク)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] University of Southern Denmark(デンマーク)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Diet intake control is indispensable for the gluconeogenic response to sodium-glucose cotransporter 2 inhibition in male mice2021

    • Author(s)
      Hashiuchi E, Watanabe H, Kimura K, Matsumoto M, Inoue H, Inaba Y
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 12 Issue: 1 Pages: 35-47

    • DOI

      10.1111/jdi.13319

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle2021

    • Author(s)
      Egami Riku、Kokaji Toshiya、Hatano Atsushi、et al.
    • Journal Title

      iScience

      Volume: 24 Issue: 3 Pages: 102217-102217

    • DOI

      10.1016/j.isci.2021.102217

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] GCN2 regulates pancreatic β-cell mass by sensing intracellular amino acid levels.2020

    • Author(s)
      Kanno A, Asahara SI, Furubayashi A, Masuda K, Yoshitomi R, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Bartolome A, Hirota Y, Yokoi N, Inaba Y, Inoue H, Matsumoto M, Inoue K, Abe T, Wei FY, Tomizawa K, Ogawa W, Seino S, Kasuga M, Kido Y.
    • Journal Title

      JCI Insight.

      Volume: 5 Issue: 9 Pages: 128820-128820

    • DOI

      10.1172/jci.insight.128820

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hollow fiber-combined glucose-responsive gel technology as an in vivo electronics-free insulin delivery system.2020

    • Author(s)
      Matsumoto A, Kuwata H, Kimura S, Matsumoto H, Ochi K, Moro-oka Y, Watanabe A, Yamada H, Ishii H, Miyazawa T, Chen S, Baba T, Yoshida H, Nakamura T, Inoue H, Ogawa Y, Tanaka M, Miyahara Y, Suganami T.
    • Journal Title

      Commun. Biol.

      Volume: 3 Issue: 1 Pages: 313-313

    • DOI

      10.1038/s42003-020-1026-x

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity2020

    • Author(s)
      Kokaji Toshiya、Hatano Atsushi、Ito Yuki、et al.
    • Journal Title

      Science Signaling

      Volume: 13 Issue: 660 Pages: 1236-1236

    • DOI

      10.1126/scisignal.aaz1236

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MAPK Erk5 in leptin receptor-expressing neurons controls body weight and systemic energy homeostasis in female mice.2019

    • Author(s)
      Horie T, Park G, Inaba Y, Hashiuchi E, Iezaki T, Tokumura K, Fukasawa K, Yamada T, HiraiwaM, Kitaguchi Y, Kamada H, Kaneda K, Tanaka T, Inoue H, Hinoi E.
    • Journal Title

      Endocrinology

      Volume: 160 Issue: 12 Pages: 2837-2848

    • DOI

      10.1210/en.2019-00090

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatic gluconeogenic response to single and long-term SGLT2 inhibition in lean/obese male hepatic G6pc-reporter mice.2019

    • Author(s)
      Inaba Y, Hashiuchi E, Watanabe H, Kimura K, Sato M, Kobayashi M, Matsumoto M, Kitamura T, Kasuga M, Inoue H.
    • Journal Title

      Endocrinology

      Volume: 160 Issue: 12 Pages: 2811-2824

    • DOI

      10.1210/en.2019-00422

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Logical design of oral glucose ingestion pattern minimizing blood glucose in humans.2019

    • Author(s)
      Fujii M, Murakami Y, Karasawa Y, Sumitomo Y, Fujita S, Koyama M, Uda S, Kubota H, Inoue H, Konishi K, Oba S, Ishii S, Kuroda S.
    • Journal Title

      NPJ Syst Biol Appl.

      Volume: 5 Issue: 1 Pages: 31-31

    • DOI

      10.1038/s41540-019-0108-1

    • NAID

      120006939199

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nicotinic alpha‐7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non‐alcoholic steatohepatitis2019

    • Author(s)
      Kimura Kumi、Inaba Yuka、Watanabe Hitoshi、Matsukawa Toshiya、Matsumoto Michihiro、Inoue Hiroshi
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 10 Issue: 3 Pages: 659-666

    • DOI

      10.1111/jdi.12964

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 肝臓SIRT2活性の低下が肥満・2型糖尿病モデルでの肝臓糖取り込み障害を引き起こす2019

    • Author(s)
      井上啓
    • Journal Title

      Diabetes Update

      Volume: 8 Pages: 14-17

    • Related Report
      2018 Research-status Report
  • [Journal Article] Dietary mung bean protein reduces high-fat diet-induced weight gain by modulating host bile acid metabolism in a gut microbiota-dependent manner.2018

    • Author(s)
      Nakatani A, Li X, Miyamoto J, Igarashi J, Watanabe H, Sutou A, Watanabe K, Motoyama T, Tachibana N, Kohno M, Inoue H, Kimura I.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 501 Issue: 4 Pages: 955-961

    • DOI

      10.1016/j.bbrc.2018.05.090

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dietary soybean protein ameliorates high-fat diet-induced obesity by modifying the gut microbiota-dependent biotransformation of bile acids.2018

    • Author(s)
      Watanabe K, Igarashi M, Li X, Nakatani A, Miyamoto J, Inaba Y, Sutou A, Saito T, Sato T, Tachibana N, Inoue H, Kimura I.
    • Journal Title

      PLoS One.

      Volume: 13 Issue: 8 Pages: e0202083-e0202083

    • DOI

      10.1371/journal.pone.0202083

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.2018

    • Author(s)
      Yano H, Sakai M, Matsukawa T, Yagi T, Naganuma T, Mitsushima M, Iida S, Inaba Y, Inoue H, Unoki-Kubota H, Kaburagi Y, Asahara S, Kido Y, Minami S, Kasuga M, Matsumoto M.
    • Journal Title

      Sci Rep.

      Volume: 8 Issue: 1 Pages: 14290-14290

    • DOI

      10.1038/s41598-018-32575-z

    • NAID

      120006529679

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Role of Brain-liver cross-talk in glucose homeostasis and its deterioration2021

    • Author(s)
      井上啓
    • Organizer
      第98回日本生理学会大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 臓器連関と肥満2021

    • Author(s)
      井上啓
    • Organizer
      第41回日本肥満学会・第38回日本肥満症治療学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Hepatic gluconeogenic response to SGLT2 inhibition in hepatic G6pc-reporter mice with NAFLD2020

    • Author(s)
      Hashiuchi E, Inaba Y, Inoue H
    • Organizer
      The Keystone Symposium on Obesity and NAFLD
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Investigation of a preventive method for non-alcoholic fatty liver disease by food materials2019

    • Author(s)
      Inoue H, Watanabe H, Inaba Y
    • Organizer
      The 7th International Conference on Food Factors
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Role of GKRP in impeded hepatic glucose uptake in type 2 diabetes2019

    • Author(s)
      Inoue H
    • Organizer
      ATLAS symposium 2019 Tissue Plasticity of Obesity
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 視床下部による肝糖産生の調節とその異常2019

    • Author(s)
      井上啓
    • Organizer
      第40回日本臨床薬理学会学術総会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] NAFLDにおける肝糖取り込み障害のメカニズムと役割2019

    • Author(s)
      井上啓、渡邉一史、稲葉有香
    • Organizer
      第6回 肝臓と糖尿病・代謝研究会・第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Central insulin action and hepatic glucose metabolism2019

    • Author(s)
      Inoue H
    • Organizer
      9th Federation of the Asian and Oceanian Pysiological Societies (FAOPS) Congress
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脳肝連関による糖代謝恒常性維持とその破綻2018

    • Author(s)
      井上啓
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Vagal regulation of hepatic glucose metabolism and its disorder2018

    • Author(s)
      Inoue H
    • Organizer
      41st Annual Meeting of the Molecular Biology Society of Japan
    • Related Report
      2018 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
      2020 Annual Research Report
  • [Remarks] 金沢大学新学術創成研究機構革新的統合バイオ研究コア栄養・代謝研究ユニット

    • URL

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

    • Related Report
      2019 Research-status Report
  • [Remarks] 金沢大学新学術創成研究機構革新的統合バイオ研究コア栄養・代謝研究ユニット

    • URL

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

    • Related Report
      2018 Research-status Report

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Published: 2018-07-20   Modified: 2022-12-28  

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