脂肪酸による新規ミトコンドリア機能制御機構の解明と生活習慣病の予防・治療への応用

• Project/Area Number: 21H03371
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: University of Tsukuba
• Principal Investigator: 松坂 賢 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: ¥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: 脂肪酸伸長酵素 / ミトコンドリア / 肝臓 / 脂肪組織

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 Annual Research Achievements

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。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・品質管理における脂肪酸伸長酵素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している。遺伝性肥満モデルob/obマウスと肝細胞特異的Elovl6欠損マウス（LKOマウス）の交配動物を作製し、肝臓のリピドミクス解析により、ob/obマウスに比べてob/ob-LKOマウスの肝臓で増加する脂質分子種の中にミトコンドリア固有のリン脂質であるカルジオリピン（CL）が多く認められ、ob/obマウスの肝臓で認められるミトコンドリアの形態的・機能的異常が、ob/ob-LKOマウスの肝臓では改善することを明らかにした。また、ob/obマウスに比べてob/ob-LKOマウスの肝臓ではミトコンドリア超複合体形成に違いがあることを確認した。さらに、脂肪肝において活性化するリン脂質リモデリング酵素の1つがCLのリモデリングおよびミトコンドリア機能不全に関与し、この作用をElovl6の阻害が抑制することを明らかにした。また、褐色脂肪組織において、寒冷刺激やβ3アドレナリン受容体刺激によりElovl6の発現が増加するとともにElovl6活性に依存した脂肪酸組成変化が特にリン脂質分画で顕著に認められること、Elovl6欠損マウスではミトコンドリア活性化が減弱することを明らかにした。その代償機構として、Elovl6欠損マウスではベージュ脂肪細胞が豊富な皮下脂肪組織の重量が増加するとともに、UCP1非依存的な熱産性能が亢進することを明らかにした。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Macrophage SREBP1 regulates skeletal muscle regeneration (2024)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The fatty acid elongase Elovl6 is crucial for hematopoietic stem cell engraftment and leukemia propagation (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination (2023)
  • 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
  • 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
  • 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 Failure (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Identification of key microRNAs regulating ELOVL6 and glioblastoma tumorigenesis (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice (2022)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] ELOVL5-mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma (2022)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Wogonin, a Compound in Scutellaria baicalensis, Activates ATF4?FGF21 Signaling in Mouse Hepatocyte AML12 Cells (2022)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques (2022)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] ELOVL2 promotes cancer progression by inhibiting cell apoptosis in renal cell carcinoma (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] High protein diet-induced metabolic changes are transcriptionally regulated via KLF15-dependent and independent pathways (2021)
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF2 (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Rapid manipulation of mitochondrial morphology in a living cell with iCMM (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophages rely on extracellular serine to suppress aberrant cytokine production (2021)
  • 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
  • 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
• [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
• [Presentation] Elovl6 as a therapeutic target in NAFLD/NASH (2022)
  • 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
  • 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
• [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
  • 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
• [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
• [Remarks] 筑波大学医学医療系松坂研究室
  • URL: https://sites.google.com/view/matsuzakalab-tsukuba/home
• [Remarks] 松坂研究室
  • URL: https://sites.google.com/view/matsuzakalab-tsukuba/home