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Mechanism of lifestyle diseases with particular attentions to the brain-lipid sensing

Research Project

Project/Area Number 16K01814
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Applied health science
Research InstitutionKanazawa University

Principal Investigator

Yamashina Tetsumori  金沢大学, 医学系, 協力研究員 (60135077)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywordsサラダ油 / ヒドロキシノネナール / 脂肪毒性 / 生活習慣病 / GPR40 / Hasp70.1 / リソソーム / 細胞死 / リノール酸 / Hsp70.1 / アルツハイマー病 / 2型糖尿病 / 非アルコ-ル性脂肪性肝炎 / 多価不飽和脂肪酸 / 海馬 / 肝臓 / 膵臓 / サル / ニューロン新生 / BDNF / furin / DHA / 脳虚血
Outline of Final Research Achievements

Deep-fried foods cooked by ω-6 oil contain or intrinsically generate hydroxynonenal by peroxidation. Hydroxynonenal promotes carbonylation of Hsp70.1 proteins, with the resultant impaired ability of cells to recycle damaged proteins and stabilize the lysosomal membrane. As the ‘calpain-cathepsin hypothesis’ has been documented as a cause of ischemic and Alzheimer neuronal death, its relevance to cell death of the hypothalamus, liver, and pancreas, being related to the appetite/energy control, was studied here. The hypothalamus senses informations from both adipocyte-derived leptin and circulating free fatty acids. Since circulating fatty acids and hydroxynonenal are increased in obese subjects, the resultant overactivation of GPR40 may cause disruption of Ca2+ homeostasis and activated calpain-mediated cleavage of the carboxylated Hsp70.1 which lead to the lysosomal permeabilization/rupture to cause diverse cell death.

Academic Significance and Societal Importance of the Research Achievements

本研究では、世界的に様々な疾患モデルで追試されて来た研究代表者提唱の「カルパイン-カテプシン仮説」に基づき、ω-6系の食用油を多量に摂るヒトに好発するアルツハイマー病や非アルコール性脂肪性肝炎(NASH)及び2型糖尿病などの病因を、ヒドロキシノネナール(HNE)などの過酸化脂質に着目して究明し得た。すなわち、『酸化損傷(カルボニル化)とカルパイン切断がもたらすHsp70.1の異常に起因するリソソーム膜の破綻』をサルモデルで検証し、生活習慣病の根本原因を見直すことができた。
本研究は、生活習慣病の発症におけるω-6系サラダ油のリスクに関して、研究代表者独自の作業仮説に基づき世界初の成果をあげた。

Report

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

    (17 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (8 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 8 results,  Open Access: 8 results,  Acknowledgement Compliant: 1 results) Presentation (3 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (2 results) Patent(Industrial Property Rights) (2 results)

  • [Int'l Joint Research] マックスプランク研究所(ゲッチンゲン)(ドイツ)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] バルナ医科大学(ブルガリア)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Hsp70 interactions with membrane lipids regulate cellular functions in health and disease2019

    • Author(s)
      Zsolt Balogia, Gabrielle Multhoff, Thomas Kirkegaard Jensen, Emyr Lloyd-Evans, Tetsumori Yamashima, Marja Jaattela, John L. Harwoodh, Laszlo Vigh
    • Journal Title

      Progress in Lipid Research

      Volume: 74 Pages: 18-30

    • DOI

      10.1016/j.plipres.2019.01.004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Scourge of Vegetable Oil&; Destroyer of Nations2018

    • Author(s)
      Tetsumori Yamashina
    • Journal Title

      J Alzheimers Dis Parkinsonism

      Volume: 8-446 Issue: 04 Pages: 1-4

    • DOI

      10.4172/2161-0460.1000446

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Implication of GPR40 Signaling in the Subventricular Zone Neurogenesis after Ischemia via Cross-Talk between Neural Progenitors and Microglia.2018

    • Author(s)
      Dazortsava MY, Pyko IV, Boneva NB, Tonchev AB, Zhu H, Sawamoto K, Minabe Y, Yamashima T.
    • Journal Title

      J Alzheimers Dis Parkinsonism

      Volume: 8 Issue: 06 Pages: 454-454

    • DOI

      10.4172/2161-0460.1000454

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Why do neurons die so fast?2018

    • Author(s)
      Tetsumori Yamashima
    • Journal Title

      J Alzheimers Dis Parkinsonism

      Volume: 9-1 Issue: 01 Pages: 1-2

    • DOI

      10.4172/2161-0460.1000e136

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vegetable Oil: The Real Culprit behind Alzheimer’s Disease2017

    • Author(s)
      Tetsumori Yamashima
    • Journal Title

      J Alzheimers Dis Parkinsonism

      Volume: 7 (6) Issue: 06 Pages: 1-3

    • DOI

      10.4172/2161-0460.1000410

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Can ‘calpain-cathepsin hypothesis’ explain Alzheimer neuronal death?2016

    • Author(s)
      Tetsumori Yamashima
    • Journal Title

      Ageing Research Reviews

      Volume: 32 Pages: 169-179

    • DOI

      10.1016/j.arr.2016.05.008

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of GPR40 for fish oil PUFA-mediated BDNF synthesis in the monkey hippocampus2016

    • Author(s)
      Arumugam Mathivanan, Yoshio Minabe, Tsuguhito Ota, Naoto Nagata, Kosuke R. Shima, Tetsumori Yamashima
    • Journal Title

      J Alzheimers Dis Parkinsonism

      Volume: 6 Issue: 01 Pages: 1-12

    • DOI

      10.4172/2161-0460.1000213

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Why is hippocampal CA1 especially vulnerable to Ischemia?2016

    • Author(s)
      Hanbai Liang, Shota Kurimoto, Kosuke R Shima, Daiki Shimizu, Tsuguhito Ota, Yoshio Minabe, Tetsumori Yamashima
    • Journal Title

      SOJ Biochemistry

      Volume: 2 Issue: 1 Pages: 1-7

    • DOI

      10.15226/2376-4589/2/1/00108

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 血流改善の漢方薬「パナパール」によるアルツハイマー病の予防的治療2018

    • Author(s)
      山嶋哲盛
    • Organizer
      第27回海馬と高次脳機能学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Role of GPR40 for PUFA-mediated BDNF synthesis in the monkey hippocampus2016

    • Author(s)
      Tetsumori Yamahima, Arumugam Mathivanan
    • Organizer
      Neurosci 2016
    • Place of Presentation
      SanDiego, USA
    • Year and Date
      2016-11-16
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 'Brain-lipid sensing'からみた生活習慣病のメカニズム解明2016

    • Author(s)
      山嶋晢盛
    • Organizer
      第25回海馬と高次脳機能学会
    • Place of Presentation
      京都同志社大学
    • Year and Date
      2016-10-02
    • Related Report
      2016 Research-status Report
    • Invited
  • [Book] COOKING OIL makes Genius or Alzheimer!2017

    • Author(s)
      Tetsumori Yamashima
    • Total Pages
      192
    • Publisher
      AUSTIN MACAULEY PUBLISHERS (LONDON)
    • Related Report
      2017 Research-status Report
  • [Book] そのサラダ油があなたを殺す2016

    • Author(s)
      山嶋晢盛
    • Total Pages
      128
    • Publisher
      SBクリエイティブ
    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物2017

    • Inventor(s)
      石倉義之、山嶋哲盛
    • Industrial Property Rights Holder
      石倉義之、山嶋哲盛
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Acquisition Date
      2017
    • Related Report
      2017 Research-status Report
  • [Patent(Industrial Property Rights)] 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物2017

    • Inventor(s)
      石倉義之、  山嶋晢盛
    • Industrial Property Rights Holder
      石倉義之、  山嶋晢盛
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017-02-01
    • Acquisition Date
      2017-02-24
    • Related Report
      2016 Research-status Report

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

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