Elucidation of the action domain of polyunsaturated fatty acids to develop new drug for hypertriglyceridemia

• Project/Area Number: 16K13040
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Applied health science
• Research Institution: University of Tsukuba
• Principal Investigator: Yahagi Naoya 筑波大学, 医学医療系, 准教授 (60420246)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 多価不飽和脂肪酸 / 栄養 / 転写 / 創薬 / 生活習慣病

Outline of Final Research Achievements

The transcription factor SREBP-1 is a transcriptional regulatory factor that regulates the expression levels of various enzymes involved in triglyceride synthesis in the liver. Polyunsaturated fatty acids (PUFAs) have long been known to suppress triglyceride synthesis in the liver, and we have found that this action of PUFAs is mediated through inhibition of SREBP-1. In this study, in order to screen compounds libraries to get novel compounds that specifically act on the same mechanism as PUFAs and have a stronger SREBP-1 inhibitory effect than PUFA, stable cell line necessary for high-throughput screening was established as an assay system to be used.

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) Issue: 3 Pages: 422-433
  • DOI: 10.1002/1873-3468.12975
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry (2017)
  • Author(s): Sawada Yoshikazu、Izumida Yoshihiko、Takeuchi Yoshinori、Aita Yuichi、Wada Nobuhiro、Li EnXu、Murayama Yuki、Piao Xianying、Shikama Akito、Masuda Yukari、Nishi-Tatsumi Makiko、Kubota Midori、Sekiya Motohiro、Matsuzaka Takashi、Nakagawa Yoshimi、Shimano Hitoshi、Yahagi Naoya
  • Journal Title: Biochem Biophys Res Commun. Volume: 493 Issue: 1 Pages: 40-45
  • DOI: 10.1016/j.bbrc.2017.09.081
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Hormone-sensitive Lipase in Leptin-Promoted Fat Loss and Glucose Lowering (2017)
  • Author(s): Takanashi M, Taira Y, Okazaki S, Takase S, Kimura T, Li CC, Xu PF, Noda A, Sakata I, Kumagai H, Ikeda Y, Iizuka Y, Yahagi N, Shimano H, Osuga JI, Ishibashi S, Kadowaki T, Okazaki H
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 11 Pages: 1105-1116
  • DOI: 10.5551/jat.39552
  • NAID: 130006191603
  • ISSN: 1340-3478, 1880-3873
  • 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] The selective PPARα modulator K-877 efficiently activates the PPARα pathway and improves lipid metabolism in mice (2017)
  • 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
  • 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] 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] 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
  • 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): 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: Mol Metab Volume: 5 Issue: 11 Pages: 1092-1102
  • DOI: 10.1016/j.molmet.2016.09.004
  • NAID: 120007129266
  • Peer Reviewed / Open Access
• [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] 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 「食の代謝・進化から迫る生命の戦略」：エネルギー欠乏への対応戦略 (2018)
  • Author(s): 矢作直也
  • Organizer: 日本農芸化学会2018年度大会
  • Invited
• [Presentation] 「栄養シグナルと生体応答」：「栄養シグナル」による遺伝子発現調節 (2017)
  • Author(s): 矢作直也
  • Organizer: 第39回日本臨床栄養学会総会・第38回日本臨床栄養協会総会
  • Invited
• [Presentation] KLF15は絶食時に中性脂肪合成から糖新生への速やかな切り替えを可能にする (2017)
  • Author(s): 武内謙憲, 矢作直也, 會田雄一, 村山友樹, 朴賢英, 沢田義一, 志鎌明人, 升田紫,泉田欣彦, 関谷元博, 松坂賢, 中川嘉, 川上康, 島野仁
  • Organizer: 第39回日本臨床栄養学会総会・第38回日本臨床栄養協会総会
• [Presentation] 中性脂肪合成を制御する転写複合体の解明 (2017)
  • Author(s): 矢作直也
  • Organizer: 第49回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] 脂肪酸分画を診療に生かす (2017)
  • Author(s): 矢作直也
  • Organizer: 第49回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] KLF15は絶食時において脂質代謝と糖代謝を抑制する重要な因子である (2017)
  • Author(s): 武内謙憲, 矢作直也, 會田雄一, 村山友樹, 沢田義一, 朴賢英, 志鎌明人, 升田紫, 泉田欣彦, 関谷元博, 松坂賢, 中川嘉, 川上康, 山田信博, 島野仁
  • Organizer: 第49回日本動脈硬化学会総会・学術集会
• [Presentation] 糖質・脂質酸エネルギー基質動員に関する協調制御機構の解明 (2017)
  • Author(s): 和田亘弘, 泉田欣彦, 矢作直也, 升田紫, 李恩旭, 沢田義一, 武内謙憲, 島野仁, 門脇孝
  • Organizer: 第71回日本栄養・食糧学会大会
• [Presentation] 多価不飽和脂肪酸（PUFA）によるSREBP-1特異的な抑制機序の解明 (2017)
  • Author(s): 升田紫, 矢作直也, 武内謙憲, 沢田義一, 朴賢英, 會田雄一, 戸谷直樹, 大屋友華里, 志鎌明人, 西真貴子, 泉田欣彦, 飯塚陽子, 位高啓史, 片岡一則, 島野仁, 門脇孝
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 2型糖尿病に関連したTCF7L2遺伝子の一塩基多型の機能分析 (2017)
  • Author(s): 朴賢英, 矢作直也, 武内謙憲, 會田雄一, 村山友樹, 沢田義一, 志鎌明人, 升田紫,泉田欣彦, 関谷元博, 松坂賢, 中川嘉, 川上康, 島野仁
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] KLF15は絶食時において脂質代謝と糖代謝を制御する重要な因子である (2017)
  • Author(s): 武内謙憲, 矢作直也, 會田雄一, 村山友樹, 沢田義一, 朴賢英, 志鎌明人, 升田紫,泉田欣彦, 関谷元博, 松坂賢, 中川嘉, 川上康, 山田信博, 島野仁
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 脂肪酸エネルギー基質動員の優先性を制御する分子基盤の探求 新規エネルギーセンサーの探索 (2017)
  • Author(s): 泉田欣彦, 和田亘弘, 矢作直也, 武内謙憲, 李恩旭, 升田紫, 沢田義一, 戸谷直樹, 朴賢英, 會田雄一, 志鎌明人, 飯塚陽子, 島野仁, 門脇孝
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry. (2017)
  • Author(s): 沢田義一, 泉田欣彦, 武内謙憲, 會田雄一, 和田亘弘, 李恩旭, 村山友樹, 朴賢英, 志鎌明人, 升田紫, 西真貴子, 久保田みどり, 関谷元博, 松坂賢, 中川嘉, 島野仁, 矢作直也
  • Organizer: 第40回日本分子生物学会年会・第90回日本生化学会大会(ConBio2017)
• [Presentation] KLF15は絶食時において脂質代謝と糖代謝を制御する重要な因子である (2016)
  • Author(s): 武内謙憲, 矢作直也, 會田雄一, 村山友樹, 沢田義一, 朴賢英, 戸谷直樹, 大屋友華里, 志鎌明人, 西真貴子, 升田紫, 久保田みどり, 泉田欣彦, 関谷元博, 松坂賢, 中川嘉, 川上康, 山田信博, 島野仁
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] 大血管障害予防に向けたLDL-C管理目標値 (2016)
  • Author(s): 矢作直也
  • Organizer: 第31回日本糖尿病合併症学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] n-3系多価不飽和脂肪酸と脂質異常症・動脈硬化 (2016)
  • Author(s): 矢作直也
  • Organizer: 第48回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-07-14
  • Invited
• [Book] 実験医学増刊「遺伝子制御の新たな主役 栄養シグナル」 (2016)
  • Author(s): 矢作直也
  • Total Pages: 231
  • Publisher: 羊土社
• [Remarks] 筑波大学医学医療系 ニュートリゲノミクスリサーチグループ
  • URL: http://nyahagi.wixsite.com/ngrg