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Elucidation of the novel regulatory mechanism of mitochondrial function by fatty acids and its application to prevention and treatment of lifestyle-related diseases

Research Project

Project/Area Number 21H03371
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 59040:Nutrition science and health science-related
Research InstitutionUniversity of Tsukuba

Principal Investigator

Matsuzaka Takashi  筑波大学, 医学医療系, 教授 (70400679)

Co-Investigator(Kenkyū-buntansha) 大野 博  筑波大学, 医学医療系, 助教 (20847909)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords脂肪酸 / ミトコンドリア / 肝臓 / 脂肪組織 / 脂肪酸伸長酵素
Outline of Research at the Start

生活習慣病の発症原因としてミトコンドリア機能障害が注目されている。申請者らは、脂肪酸伸長酵素Elovl6の研究から、肝臓におけるElovl6の欠損が脂肪肝にともなうミトコンドリア障害を改善すること、エネルギー燃焼型脂肪細胞であるベージュ細胞におけるミトコンドリア活性化にElovl6が必須であることを見出した。本研究では、脂肪肝およびベージュ脂肪細胞のミトコンドリアの形態・機能・品質管理におけるElovl6の意義を明らかにし、肥満、非アルコール性脂肪性肝疾患、2型糖尿病をはじめとした生活習慣病やミトコンドリア機能障害を基盤とした様々な疾患の病態基盤の解明や新規予防法・治療法の開発を目指す。

Outline of Final Research Achievements

Deletion of Elovl6 in the liver of ob/ob mice, a mouse model of obesity, increased numerous molecular species of cardiolipin, a mitochondria-specific phospholipid, and improved liver mitochondrial morphology and function. In addition, β3-adrenergic receptor stimulation increased Elovl6 expression in brown and beige adipocytes and altered the fatty acid composition of mitochondrial phospholipids. Elovl6 knockout mice had reduced mitochondrial function in brown adipose tissue, and as a compensatory mechanism, beige adipocytes were activated by enhancing UCP1-independent heat production via creatine biosynthesis pathway.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた成果を元にElovl6による新規ミトコンドリア機能制御機構をさらに解明することができれば、肥満、非アルコール性脂肪性肝疾患(NAFLD)、2型糖尿病をはじめとした生活習慣病の新しい分子病態の解明や、ミトコンドリアの機能低下やカルジオリピンの減少によって引き起こされる疾患の新規予防法・治療法の開発への応用が期待される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (32 results)

All 2024 2023 2022 2021 Other

All Journal Article (23 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 23 results,  Open Access: 21 results) Presentation (7 results) (of which Invited: 2 results) Remarks (2 results)

  • [Journal Article] Macrophage SREBP1 regulates skeletal muscle regeneration2024

    • Author(s)
      Oishi Yumiko、Koike Hiroyuki、Kumagami Naoki、Nakagawa Yoshimi、Araki Masaya、Taketomi Yoshitaka、Miki Yoshimi、Matsuda Shigeru、Kim Hyeree、Matsuzaka Takashi、Ozawa Hitoshi、Shimano Hitoshi、Murakami Makoto、Manabe Ichiro
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1251784-1251784

    • DOI

      10.3389/fimmu.2023.1251784

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The fatty acid elongase Elovl6 is crucial for hematopoietic stem cell engraftment and leukemia propagation2023

    • Author(s)
      Kiyoki Yusuke、Kato Takayasu、Kito Sakura、Matsuzaka Takashi、Morioka Shin、Sasaki Junko、Makishima Kenichi、Sakamoto Tatsuhiro、Nishikii Hidekazu、Obara Naoshi、Sakata-Yanagimoto Mamiko、Sasaki Takehiko、Shimano Hitoshi、Chiba Shigeru
    • Journal Title

      Leukemia

      Volume: 37 Issue: 4 Pages: 910-913

    • DOI

      10.1038/s41375-023-01842-y

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity2023

    • Author(s)
      Saito K, Sekiya M, Kainoh K, Yoshino R, Hayashi A, Han SI, Araki M, Ohno H, Takeuchi Y, Tsuyuzaki T, Yamazaki D, Wanpei C, Hada L, Watanabe S, Paramita Adi Putri PI, Murayama Y, Sugano Y, Osaki Y, Iwasaki H, Yahagi N, Suzuki H, Miyamoto T, Matsuzaka T, Shimano H.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 299 Issue: 7 Pages: 104890-104890

    • DOI

      10.1016/j.jbc.2023.104890

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function2023

    • Author(s)
      Sekiya M, Ma Y, Kainoh K, Saito K, Yamazaki D, Tsuyuzaki T, Chen W, Adi Putri PIP, Ohno H, Miyamoto T, Takeuchi Y, Murayama Y, Sugano Y, Osaki Y, Iwasaki H, Yahagi N, Suzuki H, Motomura K, Matsuzaka T, Murata K, Mizuno S, Takahashi S, Shimano H.
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 8 Pages: 112914-112914

    • DOI

      10.1016/j.celrep.2023.112914

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination2023

    • Author(s)
      Garcia Corrales AV, Verberk SGS, Haidar M, Grajchen E, Dehairs J, Vanherle S, Loix M, Weytjens T, Gervois P, Matsuzaka T, Lambrichts I, Swinnen JV, Bogie JFJ, Hendriks JJA.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 120 Issue: 37

    • DOI

      10.1073/pnas.2301030120

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Macrophage specific restoration of the Nrf2 gene in whole-body knockout mice ameliorates steatohepatitis induced by lipopolysaccharide from Porphyromonas gingivalis through enhanced hepatic clearance.2023

    • Author(s)
      K.Chihara, K.Okada, F.Uchida, I.Miura, S.Komine, E.Warabi, T.Takayama, H.Suzuki, T.Matsuzaka, N.Ishibashi-Kanno, K.Yamagata, T.Yanagawa, H.Bukawa, J.Shoda.
    • Journal Title

      PLoS One

      Volume: 18 Issue: 10 Pages: e0291880-e0291880

    • DOI

      10.1371/journal.pone.0291880

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Single-Cell Transcriptome Profiling of Pancreatic Islets From Early Diabetic Mice Identifies Anxa10 for Ca2+ Allostasis Toward β-Cell Failure2023

    • Author(s)
      Motomura K, Matsuzaka T, Shichino S, Ogawa T, Pan H, Nakajima T, Asano Y, Okayama T, Takeuchi T, Ohno H, Han SI, Miyamoto T, Takeuchi Y, Sekiya M, Sone H, Yahagi N, Nakagawa Y, Oda T, Ueha S, Ikeo K, Ogura A, Matsushima K, Shimano H.
    • Journal Title

      Diabetes

      Volume: 73 Issue: 1 Pages: 75-92

    • DOI

      10.2337/db23-0212

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids2023

    • Author(s)
      Han Song-Iee、Nakakuki Masanori、Nakagawa Yoshimi、Takeda Hiroyuki、Mizunoe Yuhei、Kainoh Kenta、Murayama Yuki、Aita Yuichi、Takeuchi Yoshinori、Osaki Yoshinori、Miyamoto Takafumi、Sekiya Motohiro、Matsuzaka Takashi、Yahagi Naoya、Sone Hirohito、Daitoku Hiroaki、Sato Ryuichiro、Kawano Hiroyuki、Shimano Hitoshi
    • Journal Title

      PNAS Nexus

      Volume: 2 Issue: 11 Pages: 1-14

    • DOI

      10.1093/pnasnexus/pgad351

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of key microRNAs regulating ELOVL6 and glioblastoma tumorigenesis2023

    • Author(s)
      Istiqamah Nurani、Matsuzaka Takashi、Shimizu Momo、Motomura Kaori、Ohno Hiroshi、Hasebe Shiho、Sharma Rahul、Okajima Yuka、Matsuda Erika、Han Song-Iee、Mizunoe Yuhei、Osaki Yoshinori、Aita Yuichi、Suzuki Hiroaki、Sone Hirohito、Takeuchi Yoshinori、Sekiya Motohiro、Yahagi Naoya、Nakagawa Yoshimi、Shimano Hitoshi
    • Journal Title

      BBA Advances

      Volume: 3 Pages: 100078-100078

    • DOI

      10.1016/j.bbadva.2023.100078

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice2022

    • Author(s)
      Okajima Yuka、Matsuzaka Takashi、Miyazaki Shun、Motomura Kaori、Ohno Hiroshi、Sharma Rahul、Shimura Takuya、Istiqamah Nurani、Han Song-iee、Mizunoe Yuhei、Osaki Yoshinori、Iwasaki Hitoshi、Yatoh Shigeru、Suzuki Hiroaki、Sone Hirohito、Miyamoto Takafumi、Aita Yuichi、Takeuchi Yoshinori、Sekiya Motohiro、Shimano Hitoshi
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

      Volume: 1868 Issue: 4 Pages: 166339-166339

    • DOI

      10.1016/j.bbadis.2022.166339

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CREBH regulation of lipid metabolism through multifaceted functions that improve arteriosclerosis.2022

    • Author(s)
      Nakagawa Y, Matsuzaka T, Shimano H.
    • Journal Title

      J Diabetes Investig.

      Volume: Feb 5. Issue: 7 Pages: 1129-1131

    • DOI

      10.1111/jdi.13766

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ELOVL5-mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma2022

    • Author(s)
      Nitta Satoshi、Kandori Shuya、Tanaka Ken、Sakka Shotaro、Siga Masanobu、Nagumo Yoshiyuki、Negoro Hiromitsu、Kojima Takahiro、Mathis Bryan J.、Shimazui Toru、Miyamoto Takafumi、Matsuzaka Takashi、Shimano Hitoshi、Nishiyama Hiroyuki
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 8 Pages: 2738-2752

    • DOI

      10.1111/cas.15454

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Wogonin, a Compound in Scutellaria baicalensis, Activates ATF4?FGF21 Signaling in Mouse Hepatocyte AML12 Cells2022

    • Author(s)
      Yamada Yasunari、Saito Hodaka、Araki Masaya、Tsuchimoto Yuhei、Muroi Shin-ichi、Suzuki Kyohei、Toume Kazufumi、Kim Jun-Dal、Matsuzaka Takashi、Sone Hirohito、Shimano Hitoshi、Nakagawa Yoshimi
    • Journal Title

      Nutrients

      Volume: 14 Issue: 19 Pages: 3920-3920

    • DOI

      10.3390/nu14193920

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A case of NASH with genetic predisposition successfully treated with an SGLT2 inhibitor: a possible involvement of mitochondrial dysfunction.2022

    • Author(s)
      Nakajima R, Sekiya M, Furuta Y, Miyamoto T, Sato M, Fukuda K, et, al.
    • Journal Title

      Endocrinol Diabetes Metab Case Rep.

      Volume: 22 Pages: 0368-0368

    • DOI

      10.1530/edm-22-0368

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques2022

    • Author(s)
      Nagatake T, Kishino S, Urano E, et al.
    • Journal Title

      Mucosal Immunology

      Volume: 15 Issue: 2 Pages: 289-300

    • DOI

      10.1038/s41385-021-00477-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] FoxO-KLF15 pathway switches the flow of macronutrients under the control of insulin.2021

    • Author(s)
      Takeuchi Y, Yahagi N, Aita Y, Mehrazad-Saber Z, Ho MH, Huyan Y, Murayama Y, Shikama A, Masuda Y, Izumida Y, Miyamoto T, Matsuzaka T, Kawakami Y, Shimano H.
    • Journal Title

      iScience.

      Volume: 24(12) Pages: 103446-103446

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ELOVL2 promotes cancer progression by inhibiting cell apoptosis in renal cell carcinoma2021

    • Author(s)
      Tanaka Ken、Kandori Shuya、Sakka Shotaro、Nitta Satoshi、Tanuma Kozaburo、Shiga Masanobu、Nagumo Yoshiyuki、Negoro Hiromitsu、Kojima Takahiro、Mathis Bryan、Shimazui Toru、Watanabe Makoto、Sato Taka-Aki、Miyamoto Takafumi、Matsuzaka Takashi、Shimano Hitoshi、Nishiyama Hiroyuki
    • Journal Title

      Oncology Reports

      Volume: 47 Issue: 2 Pages: 23-23

    • DOI

      10.3892/or.2021.8234

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis2021

    • Author(s)
      Sekiya Motohiro、Kainoh Kenta、Sugasawa Takehito、Yoshino Ryunosuke、Hirokawa Takatsugu、Tokiwa Hiroaki、Nakano Shogo、Nagatoishi Satoru、Tsumoto Kouhei、Takeuchi Yoshinori、Miyamoto Takafumi、Matsuzaka Takashi、Shimano Hitoshi
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 1-19

    • DOI

      10.1038/s41467-021-26638-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High protein diet-induced metabolic changes are transcriptionally regulated via KLF15-dependent and independent pathways2021

    • Author(s)
      Mehrazad Saber Zahra、Takeuchi Yoshinori、Sawada Yoshikazu、Aita Yuichi、Ho Man Hei、Karkoutly Samia、Tao Duhan、Katabami Kyoka、Ye Chen、Murayama Yuki、Shikama Akito、Masuda Yukari、Izumida Yoshihiko、Miyamoto Takafumi、Matsuzaka Takashi、Sugasawa Takehito、Takekoshi Kazuhiro、Kawakami Yasushi、Shimano Hitoshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 582 Pages: 35-42

    • DOI

      10.1016/j.bbrc.2021.10.027

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum lactate dehydrogenase level as a possible predictor of treatment preference in psoriasis.2021

    • Author(s)
      Koguchi-Yoshioka H, Watanabe R, Matsumura Y, Ishitsuka Y, Inoue S, Furuta J, Nakamura Y, Okiyama N, Matsuzaka T, Shimano H, Fujisawa Y, Fujimoto M.
    • Journal Title

      J Dermatol Sci.

      Volume: 103(2) Issue: 2 Pages: 109-115

    • DOI

      10.1016/j.jdermsci.2021.07.007

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF22021

    • Author(s)
      Kainoh Kenta、Takano Ryo、Sekiya Motohiro、Saito Kenji、Sugasawa Takehito、Ma Yang、Murayama Yuki、Sugano Yoko、Osaki Yoshinori、Iwasaki Hitoshi、Takeuchi Yoshinori、Yahagi Naoya、Suzuki Hiroaki、Miyamoto Takafumi、Nakagawa Yoshimi、Matsuzaka Takashi、Shimano Hitoshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 562 Pages: 146-153

    • DOI

      10.1016/j.bbrc.2021.05.069

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rapid manipulation of mitochondrial morphology in a living cell with iCMM2021

    • Author(s)
      Miyamoto Takafumi、Uosaki Hideki、Mizunoe Yuhei、Han Song-Iee、Goto Satoi、Yamanaka Daisuke、Masuda Masato、Yoneyama Yosuke、Nakamura Hideki、Hattori Naoko、Takeuchi Yoshinori、Ohno Hiroshi、Sekiya Motohiro、Matsuzaka Takashi、Hakuno Fumihiko、Takahashi Shin-Ichiro、Yahagi Naoya、Ito Koichi、Shimano Hitoshi
    • Journal Title

      Cell Reports Methods

      Volume: 1 Issue: 4 Pages: 100052-100052

    • DOI

      10.1016/j.crmeth.2021.100052

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Macrophages rely on extracellular serine to suppress aberrant cytokine production2021

    • Author(s)
      Kurita Kento、Ohta Hiroya、Shirakawa Ibuki、Tanaka Miyako、Kitaura Yasuyuki、Iwasaki Yorihiro、Matsuzaka Takashi、Shimano Hitoshi、Aoe Seiichiro、Arima Hiroshi、Ogawa Yoshihiro、Ito Ayaka、Suganami Takayoshi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 11137-11137

    • DOI

      10.1038/s41598-021-90086-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 脂肪酸伸長酵素Elovl6の欠損は脂肪肝におけるミトコンドリア異常を改善する2023

    • Author(s)
      松坂賢、林昭夫、島野仁
    • Organizer
      第65回日本脂質生化学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 脂肪肝における脂質分子種の変化とミトコンドリア恒常性の破綻2023

    • Author(s)
      松坂賢、島野仁
    • Organizer
      第96回日本生化学大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Elovl6 as a therapeutic target in NAFLD/NASH2022

    • Author(s)
      松坂賢、島野仁
    • Organizer
      第65回日本糖尿病学会年次学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 脂肪酸伸長酵Elovl6の欠損は脂肪肝におけるミトコンドリア異常を改善する2022

    • Author(s)
      松坂賢、林昭夫、島野仁
    • Organizer
      第8回肝臓と糖尿病・代謝研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 脂肪酸伸長酵素Elovl6による脂質の質の制御とメタボリックシンドローム2021

    • Author(s)
      松坂賢
    • Organizer
      第94回日本生化学大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] in vivo live imaging による膵ランゲルハンス氏島の血流解析2021

    • Author(s)
      松坂賢、岡島由佳、宮崎俊、本村香織、富田勉、島野仁
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] in vivo live imaging による膵ランゲルハンス氏島の血流解析2021

    • Author(s)
      松坂賢、岡島由佳、宮崎俊、本村香織、富田勉、島野仁
    • Organizer
      第94回日本内分泌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Remarks] 筑波大学医学医療系松坂研究室

    • URL

      https://sites.google.com/view/matsuzakalab-tsukuba/home

    • Related Report
      2023 Annual Research Report
  • [Remarks] 松坂研究室

    • URL

      https://sites.google.com/view/matsuzakalab-tsukuba/home

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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