Elucidation of the usefulness of the control of fatty acid composition for the prevention of lifestyle-related disease and application to health science

• Project/Area Number: 15H03093
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied health science
• Research Institution: University of Tsukuba
• Principal Investigator: Matsuzaka Takashi 筑波大学, 医学医療系, 准教授 (70400679)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 脂肪酸伸長酵素 / 生活習慣病 / インスリン感受性 / 糖尿病 / 脂肪組織 / 脂質 / 栄養学 / 脂肪酸

Outline of Final Research Achievements

Liver-specific Elovl6 KO mice showed enhanced hepatic insulin signaling when they were fed a high-sucrose diet or were crossed with ob/ob mice. Through transcriptome and lipidomics analysis, we identified and characterized gene X and lipid Y as hepatic insulin signaling regulators. To define the role of Elovl6 in type 2 diabetes development, we assessed the effects of Elovl6 deletion in leptin receptor-deficient C57BL/KsJ db/db mice. The db/db-Elovl6 KO mice had a markedly increased β-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. Elovl6 is a fundamental factor linking dysregulated lipid metabolism to β-cell dysfunction, islet inflammation, and β-cell apoptosis in diabetes. Moreover, we analyzed the role of Elovl6 in macrophage and found the possibility that macrophage Elovl6 regulate the formation of beige fat.

Research Products

• [Journal Article] A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C-FOS in hepatocytes. (2018)
  • Author(s): Piao X, Yahagi N, Takeuchi Y, Aita Y, Murayama Y, Sawada Y, Shikama A, Masuda Y, Nishi-Tatsumi M, Kubota M, Izumida Y, Sekiya M, Matsuzaka T, Nakagawa Y, Sugano Y, Iwasaki H, Kobayashi K, Yatoh S, Suzuki H, Yagyu H, Kawakami Y, Shimano H.
  • Journal Title: FEBS Lett. Volume: 592(3) Pages: 422-433
  • Peer Reviewed
• [Journal Article] Novel non-alcoholic steatohepatitis model with histopathological and insulin-resistant features. (2018)
  • Author(s): Owada Y, Tamura T, Tanoi T, Ozawa Y, Shimizu Y, Hisakura K, Matsuzaka T, Shimano H, Nakano N, Sakashita S, Matsukawa T, Isoda H, Ohkohchi N.
  • Journal Title: Pathol Int. Volume: 68(1) Issue: 1 Pages: 12-22
  • DOI: 10.1111/pin.12612
  • NAID: 120007134624
  • Peer Reviewed
• [Journal Article] Elovl6 Deficiency Improves Glycemic Control in Diabetic db / db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity (2017)
  • Author(s): Zhao Hui、Matsuzaka Takashi、Nakano Yuta、Motomura Kaori、Tang Nie、Yokoo Tomotaka、Okajima Yuka、Han Song-iee、Takeuchi Yoshinori、Aita Yuichi、Iwasaki Hitoshi、Yatoh Shigeru、Suzuki Hiroaki、Sekiya Motohiro、Yahagi Naoya、Nakagawa Yoshimi、Sone Hirohito、Yamada Nobuhiro、Shimano Hitoshi
  • Journal Title: Diabetes Volume: 66 Issue: 7 Pages: 1833-1846
  • DOI: 10.2337/db16-1277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling (2017)
  • Author(s): Muranaka H、Hayashi A、Minami K、Kitajima S、Kohno S、Nishimoto Y、Nagatani N、Suzuki M、Kulathunga L A N、Sasaki N、Okada N、Matsuzaka T、Shimano H、Tada H、Takahashi C
  • Journal Title: Oncogenesis Volume: 6 Issue: 6 Pages: e350-e350
  • DOI: 10.1038/oncsis.2017.51
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A key role of nuclear factor Y in the refeeding response of fatty acid synthase in adipocytes. (2017)
  • Author(s): Nishi-Tatsumi M, Yahagi N, Takeuchi Y, Toya N, Takarada A, Murayama Y, Aita Y, Sawada Y, Piao X, Oya Y, Shikama A, Masuda Y, Kubota M, Izumida Y, Matsuzaka T, Nakagawa Y, Sekiya M, Iizuka Y, Kawakami Y, Kadowaki T, Yamada N, Shimano H.
  • Journal Title: FEBS Lett Volume: 591 Issue: 7 Pages: 965-978
  • DOI: 10.1002/1873-3468.12620
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism. (2017)
  • Author(s): Oishi Y, Spann NJ, Link VM, Muse ED, Strid T, Edillor C, Kolar MJ, Matsuzaka T, Hayakawa S, Tao J, Kaikkonen MU, Carlin AF, Lam MT, Manabe I, Shimano H, Saghatelian A, Glass CK.
  • Journal Title: Cell Metab. Volume: 25(2) Issue: 2 Pages: 412-427
  • DOI: 10.1016/j.cmet.2016.11.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elongation of Long-Chain Fatty Acid Family Member 6 (Elovl6)-Driven Fatty Acid Metabolism Regulates Vascular Smooth Muscle Cell Phenotype Through AMP-Activated Protein Kinase/Kruppel-Like Factor 4 (AMPK/KLF4) Signaling. (2016)
  • Author(s): Sunaga H, Matsui H, Anjo S, Syamsunarno MR, Koitabashi N, Iso T, Matsuzaka T, Shimano H, Yokoyama T, Kurabayashi M.
  • Journal Title: J Am Heart Assoc. Volume: 5(12)
  • Peer Reviewed / Open Access
• [Journal Article] KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting. (2016)
  • Author(s): Takeuchi Y, Yahagi N, Aita Y, Murayama Y, Sawada Y, Piao X, Toya N, Oya Y, Shikama A, Takarada A, Masuda Y, Nishi M, Kubota M, Izumida Y, Yamamoto T, Sekiya M, Matsuzaka T, Nakagawa Y, Urayama O, Kawakami Y, Iizuka Y, Gotoda T, Itaka K, Kataoka K, Nagai R, Kadowaki T, Yamada N, Lu Y, Jain MK, and Shimano H
  • Journal Title: Cell Rep. Volume: 16 Issue: 9 Pages: 2373-2386
  • DOI: 10.1016/j.celrep.2016.07.069
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Crucial Role of Elovl6 in Chondrocyte Growth and Differentiation during Growth Plate Development in Mice. (2016)
  • Author(s): Kikuchi M, Shimada M, Matsuzaka T, Ishii K, Nakagawa Y, Takayanagi M, Yamada N, Shimano H.
  • Journal Title: PLoS One. Volume: 11(7) Issue: 7 Pages: e0159375-e0159375
  • DOI: 10.1371/journal.pone.0159375
  • NAID: 120007129433
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice. (2016)
  • Author(s): Suzuki-Kemuriyama N, Matsuzaka T, Kuba M, Ohno H, Han SI, Takeuchi Y, Isaka M, Kobayashi K, Iwasaki H, Yatoh S, Suzuki H, Miyajima K, Nakae D, Yahagi N, Nakagawa Y, Sone H, Yamada N, Shimano H.
  • Journal Title: PLoS One. Volume: 11(6) Issue: 6 Pages: e0157580-e0157580
  • DOI: 10.1371/journal.pone.0157580
  • NAID: 120007135350
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a (2015)
  • Author(s): Kuba M, Matsuzaka T, Matsumori R, Saito R, Kaga N, Taka H, Ikehata K, Okada N,
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 17604-17604
  • DOI: 10.1038/srep17604
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy. (2015)
  • Author(s): Osaki Y, Nakagawa Y, Miyahara S, Iwasaki H, Ishii A, Matsuzaka T, Kobayashi K, Yatoh S, Takahashi A, Yahagi N, Suzuki H, Sone H, Ohashi K, Ishibashi S, Yamada N, Shimano H
  • Journal Title: Biochem Biophys Res Commun. Volume: 466(3) Issue: 3 Pages: 536-540
  • DOI: 10.1016/j.bbrc.2015.09.065
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 1,8-cineole ameliorates steatosis of Pten liver specific KO mice via Akt inactivation. (2015)
  • Author(s): Soichiro Murata, Koichi Ogawa, Takashi Matsuzaka, Mitsuru Chiba, Ken Nakayama, Kenichi Iwasaki, Tomohiro Kurokawa, Naoki Sano, Tomohito Tanoi, Nobuhiro Ohkohchi.
  • Journal Title: International Journal of Molecular Sciences. Volume: 16 Issue: 6 Pages: 12051-63
  • DOI: 10.3390/ijms160612051
  • Peer Reviewed / Open Access
• [Presentation] 生活習慣病における脂肪酸組成制御の重要性と脂肪酸伸長酵素Elovl6の役割 (2017)
  • Author(s): 松坂賢、島野仁
  • Organizer: 第20回日本病態栄養学会年次学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2017-01-15
  • Invited
• [Presentation] 脂肪酸伸長酵素Elovl6による脂肪酸の質の制御と異所性脂肪 (2017)
  • Author(s): 松坂 賢、島野 仁
  • Organizer: 第38回日本肥満学会
  • Invited
• [Presentation] 生活習慣病における脂肪酸組成制御の重要性と脂肪酸伸長酵素Elovl6の役割 (2017)
  • Author(s): 松坂 賢、島野 仁
  • Organizer: 日本内分泌学会 第35回内分泌代謝学サマーセミナー
  • Invited
• [Presentation] he role of fatty acid elongase in brown adipose tissue (2016)
  • Author(s): Rahul Sharma、松坂賢、本村香織、Hui Zhao、大野博、武内謙憲、矢作直也、関谷元博、中川 嘉、村谷匡史、島野仁
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウン（東京都江東区）
  • Year and Date: 2016-10-08
• [Presentation] 脂肪酸伸長酵素Elovl6欠損マウスにおけるショ糖嗜好 性亢進 (2016)
  • Author(s): 千葉恵、松坂賢、煙山紀子、籐麻里子、大野博、関谷元博、中川嘉、矢作直也、島野仁
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウン（東京都江東区）
  • Year and Date: 2016-10-07
• [Presentation] Elovl6 の欠損は胆石形成食負荷 LDL 受容体二重欠損マウスにおける脂肪性肝炎の発症を抑制するが，胆石形成を促進する (2016)
  • Author(s): 久芳素子、松坂賢、大野博、中川嘉、矢作直也、島野仁
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2016-05-21
• [Presentation] 脂肪酸伸長酵素 Elovl6 の骨・成長板発達異常の背景となる分子機序の検討 (2016)
  • Author(s): 菊地愛美、松坂賢、石井清朗、中川嘉、島野仁、嶋田昌子
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2016-05-21
• [Presentation] 脂肪酸伸長酵素Elovl6 の欠損はdb/dbマウスの2型糖尿病の発症・進展を抑制す る (2016)
  • Author(s): 趙会、松坂賢、中野雄太、唐寧、鈴木真璃衣、武内謙憲、岩崎仁、小林和人、矢藤 繁、鈴木浩明、矢作直也、中川嘉、山田信博、島野仁
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2016-04-21
• [Presentation] 脂肪酸伸長酵素Elovl6の高次脳機能における役割 (2016)
  • Author(s): 大野博、松坂賢、島野仁
  • Organizer: 第53回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-04-15
• [Presentation] 脂肪酸伸長酵素Elovl6による脂肪酸組成制御と生活習慣病 (2016)
  • Author(s): 松坂賢、島野仁
  • Organizer: 第97回 日本栄養·食糧学会 関東支部大会シンポジウム
  • Place of Presentation: 東京大学 農学部 弥生キャンパス（東京）
  • Year and Date: 2016-03-12
  • Invited
• [Presentation] 脂肪酸伸長酵素Elovl6 の欠損はdb/dbマウスの2型糖尿病の発症・進展を抑制する (2015)
  • Author(s): 趙会、松坂賢、中野雄太、唐寧、鈴木真璃衣、武内謙憲、岩崎仁、小林和人、矢藤繁、鈴木浩明、矢作直也、中川嘉、山田信博、島野仁
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋国際会議場（愛知）
  • Year and Date: 2015-10-03
• [Presentation] 脂肪酸伸長酵素Elovl6の骨・軟骨細胞における役割の検討 (2015)
  • Author(s): 菊地愛美、嶋田昌子、松坂賢、石井清朗、中川嘉、島野仁
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 海峡メッセ下関（山口）
  • Year and Date: 2015-05-22
• [Presentation] Enhanced high sucrose diet preference in Elovl6 deficient mice (2015)
  • Author(s): Mariko Toh, Noriko Suzuki-kemuriyama, Yuki Fushimi, Eriko Yoshida, Hiroshi Ohno, Junko Kato, Takashi Matsuzaka, Nobuhiro Yamada, Kaoruko Iida, Hitoshi Shimano.
  • Organizer: 12th Asian Congress of Nutrition (12th ACN)
  • Place of Presentation: Pacifico Yokohama, Japan.
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] Comparison of the effects of EPA and DHA on the development of NASH (2015)
  • Author(s): Noriko Kemuriyama, Takashi Matsuzaka, Takeuchi Yoshinori, Nakagawa Yoshimi, Yahagi Naoya, Yamada Nobuhiro, Shimano Hitoshi.
  • Organizer: 12th Asian Congress of Nutrition (12th ACN)
  • Place of Presentation: Pacifico Yokohama, Japan.
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Remarks] 筑波大学 内分泌代謝・糖尿病内科
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Remarks] 筑波大学 テニュアトラック普及・定着事業 松坂研究室
  • URL: http://matsuzakalab-tsukuba.org/
• [Remarks] http://matsuzakalab-tsukuba.org/