Identification of the multifaceted metabolic roles of SIRT7

• Project/Area Number: 16H05328
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: Yamagata Kazuya 熊本大学, 大学院生命科学研究部(医), 教授 (70324770)
• Co-Investigator(Kenkyū-buntansha): 吉澤 達也 熊本大学, 大学院生命科学研究部(医), 准教授 (40313530) ; 佐藤 叔史 熊本大学, 大学院生命科学研究部(医), 助教 (90622598)
• Research Collaborator: Sawa Tomohiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: サーチュイン / SIRT7 / 脂肪肝 / 脂肪細胞 / ＳＩＲＴ７ / 褐色脂肪細胞 / インスリン / 肝臓 / TR4 / ユビキチンリガーゼ複合体 / 褐色脂肪組織 / 糖尿病 / 褐色脂肪 / DDB1 / サーチュン / エネルギー代謝

Outline of Final Research Achievements

Sirtuin 7 (SIRT7) is an NAD+-dependent deacetylase. Recently, we found that Sirt7 knockout mice are resistant to high-fat diet-induced fatty liver, but the mechanism is not identified. Here, we demonstrate that SIRT7 binds directly to DDB1, a component of CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex and deacetylates DDB1. SIRT7-mediated deacetylation of K1121 of DDB1 attenuates the activity of the CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex by reducing binding between DDB1 and DCAF1, leading to the increased expression of TR4 and hepatic lipid accumulation.

Academic Significance and Societal Importance of the Research Achievements

アルコール非依存性に肝臓に脂肪蓄積をきたすNAFLD患者は我が国に1000万人程度存在していると推定されているが、その一部は脂肪肝炎から肝硬変、さらに肝癌と進行するため、その対策は重要な医学的課題である。我々は脱アセチル化酵素であるSIRT7のノックアウトマウスが脂肪肝を抑制することを見出しているが、その詳細な分子メカニズムは不明であった。本研究の結果、SIRT7の抑制が脂肪肝を軽減する詳細な分子機構が明らかになり、SIRT7を標的とした治療薬開発の基盤が確立された。

Research Products

• [Int'l Joint Research] Max Planck 研究所(ドイツ)
• [Int'l Joint Research] Max Planck Institute(Germany)
• [Int'l Joint Research] Max Planck Institute(Germany)
• [Journal Article] SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix (2018)
  • Author(s): Fukuda Masatoshi、Yoshizawa Tatsuya et al.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2833-2833
  • DOI: 10.1038/s41467-018-05187-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sirtuin 7 Deficiency Ameliorates Cisplatin-induced Acute Kidney Injury Through Regulation of the Inflammatory Response (2018)
  • Author(s): Miyasato Yoshikazu、Yoshizawa Tatsuya、Sato Yoshifumi、Nakagawa Terumasa、Miyasato Yuko、Kakizoe Yutaka、Kuwabara Takashige、Adachi Masataka、Ianni Alessandro、Braun Thomas、Komohara Yoshihiro、Mukoyama Masashi、Yamagata Kazuya
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5927-5927
  • DOI: 10.1038/s41598-018-24257-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis. (2018)
  • Author(s): Yamada S, Senokuchi T, Matsumura T, Morita Y, Ishii N, Fukuda K, Murakami S, Nishida S, Kawasaki S, Motoshima H, Furukawa N, Komohara Y, Fujiwara Y, Koga T, Yamagata K, Takeya M, Araki E
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 印刷中 Issue: 5 Pages: 994-1006
  • DOI: 10.1161/atvbaha.117.310320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiopoietin-like protein 2 promotes chondrogenic differentiation during bone growth as a cartilage matrix factor. (2018)
  • Author(s): Tanoue H, Morinaga J, Yoshizawa T, Yugami M, Itoh H, Nakamura T, Uehara Y, Masuda T, Odagiri H, Sugizaki T, Kadomatsu T, Miyata K, Endo M, Terada K, Ochi H, Takeda S, Yamagata K, Fukuda T, Mizuta H, Oike Y.
  • Journal Title: Osteoarthritis Cartilage Volume: 26 Issue: 1 Pages: 108-117
  • DOI: 10.1016/j.joca.2017.10.011
  • Peer Reviewed / Open Access
• [Journal Article] Sirtuin 7 is involved in the consolidation of fear memory in mice (2018)
  • Author(s): Islam Md Safiqul、Wei Fan-Yan、Ohta Kunimasa、Shigematsu Naoki、Fukuda Takaichi、Tomizawa Kazuhito、Yoshizawa Tatsuya、Yamagata Kazuya
  • Journal Title: Biochem Biophys Res Commun. Volume: 495 Issue: 1 Pages: 261-266
  • DOI: 10.1016/j.bbrc.2017.10.159
  • Peer Reviewed
• [Journal Article] Age-dependent increase in angiopoietin-like protein 2 accelerates skeletal muscle loss in mice. (2018)
  • Author(s): Zhao J, Tian Z, Kadomatsu T, Xie P, Miyata K, Sugizaki T, Endo M, Zhu S, Fan H, Horiguchi H, Morinaga J, Terada K, Yoshizawa T, Yamagata K, Oike Y.
  • Journal Title: J Biol Chem Volume: 293 Issue: 5 Pages: 1596-1609
  • DOI: 10.1074/jbc.m117.814996
  • Peer Reviewed / Open Access
• [Journal Article] SIRT7 is an important regulator of cartilage homeostasis and osteoarthritis development. (2018)
  • Author(s): Korogi W, Yoshizawa T, Karim MF, Tanoue H, Yugami M, Sobuz SU, Hinoi E, Sato Y, Oike Y, Mizuta H, Yamagata K
  • Journal Title: Biochem Biophys Res Commun Volume: 印刷中 Issue: 3 Pages: 891-897
  • DOI: 10.1016/j.bbrc.2018.01.129
  • Peer Reviewed
• [Journal Article] Hypoxia reduces HNF4alpha/MODY1 protein expression in pancreatic beta-cells by activating AMP-activated protein kinase. (2017)
  • Author(s): Sato Y, Karim MF et al.
  • Journal Title: J. Biol. Chem. Volume: 印刷中 Issue: 21 Pages: 8716-8728
  • DOI: 10.1074/jbc.m116.767574
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4 (2017)
  • Author(s): Karim MF, Yoshizawa T, Sobuz SU, Sato Y, Yamagata K
  • Journal Title: Biochem Biophys Res Commun. Volume: 490 Issue: 2 Pages: 423-428
  • DOI: 10.1016/j.bbrc.2017.06.057
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of metabolism by SIRT1 and SIRT7 (2017)
  • Author(s): Yamagata K, Yoshizawa T
  • Journal Title: Int. Rev. Cel. Mol. Bio. Volume: 335 Pages: 143-166
  • DOI: 10.1016/bs.ircmb.2017.07.009
  • Peer Reviewed
• [Journal Article] Translational repression of a splice variant of cynomolgus macaque CXCL1L by its C-terminal sequence (2017)
  • Author(s): Hisayuki Nomiyama, Naoki Osada, Ichiro Takahashi, Keiji Terao, Kazuya Yamagata, Osamu Yoshie
  • Journal Title: J. Interferon Cytokine Res. Volume: 37 Issue: 3 Pages: 129-138
  • DOI: 10.1089/jir.2016.0085
  • Peer Reviewed
• [Journal Article] Sources of variation of transthyretin in healthy subjects in East and Southeast Asia: Clinical and experimental evidence for the effect of alcohol on transthyretin metabolism. (2016)
  • Author(s): Jono H, Su Y, Obayashi K, Tanaka Y, Ishiguro A, Nishimura H, Shinriki S, Ueda M, Ikeda K, Yamagata K, Ichihara K, Ando Y; Scientific Committee for the Asia-Pacific Federation of Clinical Biochemistry.
  • Journal Title: Clin Chim Acta Volume: 458 Pages: 240-5
  • DOI: 10.1016/j.cca.2016.04.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Bhlhe40-Mafa経路を介した低酸素ストレスによるインスリン分泌抑制 (2018)
  • Author(s): 津山友徳、佐藤叔史、吉澤達也、松岡孝昭、山縣和也
  • Organizer: 第41回日本分子生物学会
• [Presentation] 低酸素応答因子HIF-1/AMPKによる膵β細胞障害の分子機構 (2018)
  • Author(s): 佐藤叔史、山縣和也
  • Organizer: 第91回日本生化学会大会
  • Invited
• [Presentation] エクソソームを介した褐色脂肪組織から肝臓への新たな生理作用の解明 (2018)
  • Author(s): 狩場佑一、吉澤達也、山縣和也
  • Organizer: 第91回日本生化学会大会
• [Presentation] 脱アシル化酵素SIRT7によるOsterixの転写活性化は骨形成に重要である (2017)
  • Author(s): 吉澤達也、福田雅俊、竹田秀、山縣和也
  • Organizer: 第90回日本内分泌学会学術総会
• [Presentation] SIRT7によるエネルギー代謝制御 (2017)
  • Author(s): 山縣和也、吉澤達也
  • Organizer: 第90回日本内分泌学会学術総会
• [Presentation] 核内脱アシル化酵素SIRT7は軟骨細胞分化を制御し、変形性膝関節症の発症に関与する (2017)
  • Author(s): 興梠 航、吉澤達也、山縣和也
  • Organizer: 第３５回日本骨代謝学会学術集会
• [Presentation] 膵β細胞低酸素によるHNF4蛋白低下メカニズムの解明 (2017)
  • Author(s): 佐藤叔史、津山友徳、佐藤ちなみ、Md. Fazlul Karim、吉澤達也、井上正宏、山縣和也
  • Organizer: 日本生化学学会九州支部例会
• [Presentation] 急性尿細管障害におけるSIRT7の機能解明 (2017)
  • Author(s): 宮里腎和、吉澤達也、中川輝政、柿添 豊、桒原孝成、安達政隆、向山政志、山縣和也
  • Organizer: 第２１回日本心血管内分泌代謝学会学術総会
• [Presentation] SIRT7とアンチエイジング (2017)
  • Author(s): 山縣和也、吉澤達也
  • Organizer: 脳心血管抗加齢研究会2017
• [Presentation] ARNTはARNT/HIF-１αによる血管形成とは独立して直接骨芽細胞の分化を促進する (2016)
  • Author(s): 福田雅俊、吉澤達也、池亀美華、竹田秀、山縣和也
  • Organizer: 第34回日本骨代謝学会学術集会
• [Presentation] 核内脱アセチル化酵素SIRT7はOsterixを介して骨形成を制御する (2016)
  • Author(s): 吉澤達也、福田雅俊、興梠航、竹田秀、山縣和也
  • Organizer: 第34回日本骨代謝学会学術集会
• [Presentation] SIRT7によるエネルギー代謝制御 (2016)
  • Author(s): 吉澤達也、山縣和也
  • Organizer: 第３７回日本肥満学会
• [Presentation] 代謝制御におけるSIRT7の多様な役割 (2016)
  • Author(s): 吉澤達也、山縣和也
  • Organizer: 第８９回日本生化学会大会
• [Presentation] Deletion of Sirtuin 7 Ameliorates Cisplatin-Induced Acute Kidney Injury through Regulation of Inflammatory Response. (2016)
  • Author(s): Yoshikazu Miyasato, Tatsuya Yoshizawa, Terumasa Nakagawa, Yutaka Kakizoe, Yuichiro Izumi, Takashige Kuwabara, Masataka Adachi, Eva Bober, Masashi Mukoyama, Kazuya Yamagata
  • Organizer: The American Society of Nephrology (ASN) Kidney Week 2016 Annual Meeting
  • Int'l Joint Research
• [Presentation] SIRT7による代謝制御作用 (2016)
  • Author(s): 山縣和也、吉澤達也
  • Organizer: 脳心血管抗加齢研究会２０１６
• [Remarks] 熊本大学大学院生命科学研究部病態生化学分野
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/biochem2/biochem2.html