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Analysis of metabolic diseases targeting nutrient complex associated inflammation caused from enterohepatic circulation

Research Project

Project/Area Number 16H03253
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied health science
Research InstitutionUniversity of Tsukuba

Principal Investigator

Nakagawa Yoshimi  筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)

Co-Investigator(Kenkyū-buntansha) 島野 仁  筑波大学, 医学医療系, 教授 (20251241)
松坂 賢  筑波大学, 医学医療系, 教授 (70400679)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Keywords腸肝循環 / CREBH / SREBP / CRISPR/Cas9システム / 動脈硬化 / 非アルコール性脂肪肝 / 生活習慣病 / 肝がん / 慢性炎症 / 脂質代謝 / CRISPR/Cas9 / FGF21 / 遺伝子発現 / 脂質 / 糖尿病 / 栄養学
Outline of Final Research Achievements

We clarified that the transcription factor CREBH could contribute to the therapeutic strategy of lifestyle-related diseases. CREBH-deficient mice developed high-fat diet-induced abnormal fatty liver, hepatitis, and small intestine structural abnormalities, and then exacerbated these diseases due to abnormal nutrition metabolism. Furthermore, we clarified that CREBH deficiency induces atherosclerosis and liver cancer, which are terminal images of lifestyle-related diseases. Furthermore, we newly generated tissue-specific CREBH overexpression / deficiency mice by creating genetically modified mice using the CRISPR / Cas9 system. Non-alcoholic fatty liver and arteriosclerosis were aggravated in even tissue-specific KO mice of the liver and small intestine. In this study, we clarified that CREBH plays a crucial role in the regulation of nutrient metabolism and nutrient absorption in the liver and small intestine, respectively, and is greatly involved in lifestyle-related diseases.

Academic Significance and Societal Importance of the Research Achievements

CREBHは小胞体ストレスに応答し、炎症反応を惹起させるという報告があった。しかしながら、我々の研究からCREBHは実際には炎症を抑えるとともに、生活習慣病改善ホルモンFGF21を介し病態を改善させる新規の生活習慣病改善に寄与する転写因子であることを明らかにした。CREBHは脂質代謝の改善にも大きく関連し、すでに治療標的となっているPPARαの活性を制御することを見出している。CREBH KOマウスではPPARα活性化薬(フィブラート))による脂質代謝改善効果が失われる。フィブラートで治療できない脂質異常症の新たな治療標的としてCREBHで有効であることを示した。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (20 results)

All 2020 2019 2018 2017 2016 Other

All Journal Article (11 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 11 results,  Open Access: 9 results,  Acknowledgement Compliant: 2 results) Presentation (5 results) (of which Invited: 1 results) Remarks (4 results)

  • [Journal Article] CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms2020

    • Author(s)
      Satoh Aoi、Han Song-iee、Araki Masaya、Nakagawa Yoshimi、Ohno Hiroshi、Mizunoe Yuhei、Kumagai Kae、Murayama Yuki、Osaki Yoshinori、Iwasaki Hitoshi、Sekiya Motohiro、Konishi Morichika、Itoh Nobuyuki、Matsuzaka Takashi、Sone Hirohito、Shimano Hitoshi
    • Journal Title

      iScience

      Volume: 23 Issue: 3 Pages: 100930-100930

    • DOI

      10.1016/j.isci.2020.100930

    • NAID

      120006891020

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice2018

    • Author(s)
      Araki Masaya、Nakagawa Yoshimi、Oishi Asayo、Han Song-iee、Wang Yunong、Kumagai Kae、Ohno Hiroshi、Mizunoe Yuhei、Iwasaki Hitoshi、Sekiya Motohiro、Matsuzaka Takashi、Shimano Hitoshi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 7 Pages: 2148-2148

    • DOI

      10.3390/ijms19072148

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CREBH Regulates Systemic Glucose and Lipid Metabolism2018

    • Author(s)
      Nakagawa Yoshimi、Shimano Hitoshi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 5 Pages: 1396-1396

    • DOI

      10.3390/ijms19051396

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular association model of PPARα and its new specific and efficient ligand, pemafibrate: Structural basis for SPPARMα2018

    • Author(s)
      Yamamoto Yuta、Takei Kenta、Arulmozhiraja Sundaram、Sladek Vladimir、Matsuo Naoya、Han Song-iee、Matsuzaka Takashi、Sekiya Motohiro、Tokiwa Takaki、Shoji Mitsuo、Shigeta Yasuteru、Nakagawa Yoshimi、Tokiwa Hiroaki、Shimano Hitoshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 499 Issue: 2 Pages: 239-245

    • DOI

      10.1016/j.bbrc.2018.03.135

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood2018

    • Author(s)
      X Yuan, K Tsujimoto, K Hashimoto, K Kawahori, N Hanzawa, M Hamaguchi, T Seki, M Nawa, T Ehara, Y Kitamura, I Hatada, M Konishi, N Itoh, Y Nakagawa, H Shimano, T Takai-Igarashi, Y Kamei, Y Ogawa.
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 636-636

    • DOI

      10.1038/s41467-018-03038-w

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Critical role of CREBH-mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells2017

    • Author(s)
      Chida Takeshi、Ito Masahiko、Nakashima Kenji、Kanegae Yumi、Aoshima Takuya、Takabayashi Shuji、Kawata Kazuhito、Nakagawa Yoshimi、Yamamoto Masahiro、Shimano Hitoshi、Matsuura Tomokazu、Kobayashi Yoshimasa、Suda Takafumi、Suzuki Tetsuro
    • Journal Title

      Hepatology

      Volume: 66 Issue: 5 Pages: 1430-1443

    • DOI

      10.1002/hep.29319

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice.2017

    • Author(s)
      Takei K, Nakagawa Y, Wang Y, Han SI, Satoh A, Sekiya M, Matsuzaka T, Shimano H.
    • Journal Title

      J Pharmacol Sci.

      Volume: 印刷中 Issue: 4 Pages: 214-222

    • DOI

      10.1016/j.jphs.2017.02.003

    • NAID

      120007128987

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The selective PPARα modulator K-877 efficiently activates the PPARα pathway and improves lipid metabolism in mice2017

    • Author(s)
      Takei K, Han SI, Murayama Y, Satoh A, Oikawa F, Ohno H, Osaki Y, Matsuzaka T, Sekiya M, Iwasaki H, Yatoh S, Yahagi N, Suzuki H, Yamada N, Nakagawa Y, Shimano H.
    • Journal Title

      Journal of Diabetes Investigation

      Volume: in press Issue: 4 Pages: 446-452

    • DOI

      10.1111/jdi.12621

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα.2016

    • Author(s)
      Nakagawa Y, Satoh A, Tezuka H, Han SI, Takei K, Iwasaki H, Yatoh S, Yahagi N, Suzuki H, Iwasaki Y, Sone H, Matsuzaka T, Yamada N, Shimano H.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 39182-39182

    • DOI

      10.1038/srep39182

    • NAID

      120007135285

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression.2016

    • Author(s)
      5.Kikuchi T, Orihara K, Oikawa F, Han SI, Kuba M, Okuda K, Satoh A, Osaki Y, Takeuchi Y, Aita Y, Matsuzaka T, Iwasaki H, Yatoh S, Sekiya M, Yahagi N, Suzuki H, Sone H, Nakagawa Y, Yamada N, Shimano H.
    • Journal Title

      Molecular Metabolism

      Volume: 5 Pages: 1092-1102

    • NAID

      120007129266

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system.2016

    • Author(s)
      Nakagawa Y, Oikawa F, Ohno H, Yagishita Y, Satoh A, Osaki Y, Takei K, Kikuchi T, Song-iee H, Mizuno S. Matsuzaka T, Iwasaki H, Kobayashi K, Yatoh S, Yahagi N, Suzuki H, Sone H, Takahashi S, Yamada N, Shimano H.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 27857-27857

    • DOI

      10.1038/srep27857

    • NAID

      120007135376

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] CREBH regulates ChREBP-mediated hepatic fructose metabolism2019

    • Author(s)
      Yunong Wang, Yoshimi Nakagawa, Song-Iee Han, Kae Kumagai, Yuhei Mizunoe, Masaya Araki, Motohiro Sekiya, Takashi Matsuzaka, Hitoshi Shimano
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脂質代謝調節転写因子と動脈硬化・糖尿病2018

    • Author(s)
      中川 嘉
    • Organizer
      第33回日本糖尿病合併症学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] The significance of CREBH on ChREBP-mediated FGF21 secretion in hepatic fructose metabolism2018

    • Author(s)
      王 雨農
    • Organizer
      第33回日本糖尿病合併症学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 脂質異常症新規治療薬 K877 の食餌誘導性肥満に対する効果2018

    • Author(s)
      荒木 雅弥、中川 嘉
    • Organizer
      第55回日本臨床分子医学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] CREB3L3欠損による動脈硬化発症の分子メカニズム2017

    • Author(s)
      中川 嘉、関谷 元博、松坂  賢、島野  仁
    • Organizer
      第32回 日本糖尿病合併症学会
    • Related Report
      2017 Annual Research Report
  • [Remarks] 筑波大学 医学医療系 内分泌代謝・糖尿病内科

    • URL

      https://www.u-tsukuba-endocrinology.jp/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 筑波大学 国際統合睡眠医科学研究機構

    • URL

      https://wpi-iiis.tsukuba.ac.jp/japanese/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 筑波大学 医学医療系 内分泌代謝・糖尿病代謝内科

    • URL

      http://www.u-tsukuba-endocrinology.jp/index.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 筑波大学 医学医療系 内分泌代謝・糖尿病内科

    • URL

      http://www.u-tsukuba-endocrinology.jp/

    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2021-02-19  

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