Analysis of SREBP-1 activation and lipid metabolism by novel protease

• Project/Area Number: 16K01811
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: University of Tsukuba
• Principal Investigator: Han Song-Iee 筑波大学, 医学医療系, 研究員 (80729541)
• Co-Investigator(Kenkyū-buntansha): 中川 嘉 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: SREBP-1 / プロテアーゼ / 脂質代謝

Outline of Final Research Achievements

SREBP-1 is the master regulator of lipid synthesis, and recently we identified a novel protease (proteaseX) that activates SREBP-1. In this study, we aimed to clarify the mechanisms of SREBP-1 activation and lipid metabolism by proteaseX.
We analyzed the mechanisms of SREBP-1 activation by overexpression or knockout of proteaseX in vitro and in vivo. We found that proteaseX activates SREBP-1 and its target lipogenic genes expressions by cleavage of SREBP-1. ProteaseX and SREBP-1 were co-localized in the ER, and proteaseX interacted with SREBP-1-SCAP-Insig complex. In mouse experiments, activated SREBP-1 and lipid synthesis genes expressions were decreased in proteaseX knockout mice on western diet (WD) compared with wild-type mice on WD. These results suggest that proteaseX is required for activating SREBP-1 and lipid metabolism in response to nutrient overload.

Academic Significance and Societal Importance of the Research Achievements

本研究により、脂質合成のマスターレギュレーターであるSREBP-1の活性化制御に新たな因子を介した経路が存在することを示すことができた。
脂質異常症などにおける過度なSREBPの活性化を抑制することは、生活習慣病の改善に繋がることから、異常なSREBPの活性を低下させる研究はとても重要であると考えられる。本研究では、プロテアーゼXが高脂肪食負荷時にSREBP-1を活性化し脂質合成酵素群の発現を誘導すること、この活性化が多価不飽和脂肪酸により抑制されるということを示した。従って、脂質異常症におけるSREBP-1活性化機構の一旦を明らかにし、その活性化抑制機構を提案することができたと考えている。

Research Products

• [Journal Article] Octacosanol and policosanol prevent high-fat diet-induced obesity and metabolic disorders by activating brown adipose tissue and improving liver metabolism (2019)
  • Author(s): Sharma Rahu, Takafumi Miyamoto, et al.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5169-5169
  • DOI: 10.1038/s41598-019-41631-1
  • NAID: 120007133465
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exercise training reduces ventricular arrhythmias through restoring calcium handling and sympathetic tone in myocardial infarction mice (2019)
  • Author(s): Qin Rujie、Murakoshi Nobuyuki、Xu DongZhu、Tajiri Kazuko、Feng Duo、Stujanna Endin N.、Yonebayashi Saori、Nakagawa Yoshimi、Shimano Hitoshi、Nogami Akihiko、Koike Akira、Aonuma Kazutaka、Ieda Masaki
  • Journal Title: Physiological Reports Volume: 7 Issue: 4 Pages: e13972-e13972
  • DOI: 10.14814/phy2.13972
  • NAID: 120007133480
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glucocorticoid receptor suppresses gene expression of Rev-erbα (Nr1d1) through interaction with the CLOCK complex (2019)
  • Author(s): Murayama Yuki, Takafumi Miyamoto, et al.
  • Journal Title: FEBS Letters Volume: 593 Issue: 4 Pages: 423-432
  • DOI: 10.1002/1873-3468.13328
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice (2018)
  • Author(s): Araki Masaya、Nakagawa Yoshimi、Oishi Asayo、Han Song-iee、Wang Yunong、Kumagai Kae、Ohno Hiroshi、Mizunoe Yuhei、Iwasaki Hitoshi、Sekiya Motohiro、Matsuzaka Takashi、Shimano Hitoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 7 Pages: 2148-2148
  • DOI: 10.3390/ijms19072148
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CREBH Regulates Systemic Glucose and Lipid Metabolism (2018)
  • Author(s): Nakagawa Yoshimi、Shimano Hitoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 5 Pages: 1396-1396
  • DOI: 10.3390/ijms19051396
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transgenic Mice Overexpressing SREBP-1a in Male ob/ob Mice Exhibit Lipodystrophy and Exacerbate Insulin Resistance. (2018)
  • Author(s): Ohno H, Matsuzaka T, Tang N, Sharma R, Motomura K, Shimura T, Satoh A, Han SI, Takeuchi Y, Aita Y, Iwasaki H, Yatoh S, Suzuki H, Sekiya M, Nakagawa Y, Sone H, Yahagi N, Yamada N, Higami Y, Shimano H.
  • Journal Title: Endocrinology. Volume: 159(6) Issue: 6 Pages: 2308-2323
  • DOI: 10.1210/en.2017-03179
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular association model of PPARα and its new specific and efficient ligand, pemafibrate: Structural basis for SPPARMα (2018)
  • Author(s): Yamamoto Yuta、Takei Kenta、Arulmozhiraja Sundaram、Sladek Vladimir、Matsuo Naoya、Han Song-iee、Matsuzaka Takashi、Sekiya Motohiro、Tokiwa Takaki、Shoji Mitsuo、Shigeta Yasuteru、Nakagawa Yoshimi、Tokiwa Hiroaki、Shimano Hitoshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 499 Issue: 2 Pages: 239-245
  • DOI: 10.1016/j.bbrc.2018.03.135
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood (2018)
  • Author(s): X Yuan, K Tsujimoto, K Hashimoto, K Kawahori, N Hanzawa, M Hamaguchi, T Seki, M Nawa, T Ehara, Y Kitamura, I Hatada, M Konishi, N Itoh, Y Nakagawa, H Shimano, T Takai-Igarashi, Y Kamei, Y Ogawa.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 636-636
  • DOI: 10.1038/s41467-018-03038-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Mitochondrial intermediate peptidase is a novel regulator of sirtuin-3 activation by caloric restriction (2017)
  • Author(s): Kobayashi Masaki、Takeda Kanae、Narita Takumi、Nagai Keita、Okita Naoyuki、Sudo Yuka、Miura Yuri、Tsumoto Hiroki、Nakagawa Yoshimi、Shimano Hitoshi、Higami Yoshikazu
  • Journal Title: FEBS Lett. Volume: 591 Issue: 24 Pages: 4067-4073
  • DOI: 10.1002/1873-3468.12914
  • NAID: 120007134579
  • 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] Critical role of CREBH-mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells (2017)
  • Author(s): Chida Takeshi、Ito Masahiko、Nakashima Kenji、Kanegae Yumi、Aoshima Takuya、Takabayashi Shuji、Kawata Kazuhito、Nakagawa Yoshimi、Yamamoto Masahiro、Shimano Hitoshi、Matsuura Tomokazu、Kobayashi Yoshimasa、Suda Takafumi、Suzuki Tetsuro
  • Journal Title: Hepatology Volume: 66 Issue: 5 Pages: 1430-1443
  • DOI: 10.1002/hep.29319
  • Peer Reviewed / Int'l Joint Research
• [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] Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice. (2017)
  • Author(s): Takei K, Nakagawa Y, Wang Y, Han SI, Satoh A, Sekiya M, Matsuzaka T, Shimano H.
  • Journal Title: J Pharmacol Sci. Volume: 印刷中 Issue: 4 Pages: 214-222
  • DOI: 10.1016/j.jphs.2017.02.003
  • NAID: 120007128987
  • 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] 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 Pages: 1092-1102
  • NAID: 120007129266
  • Peer Reviewed / Int'l Joint Research
• [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
• [Journal Article] Phosphorylation of MafA enhances interaction with Beta2/NeuroD1. (2016)
  • Author(s): Han, S.-i, Y. Tsunekage, K. Kataoka
  • Journal Title: Acta Diabetologica Volume: - Issue: 4 Pages: 651-660
  • DOI: 10.1007/s00592-016-0853-1
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] MafAはリン酸化によりBeta2/NeuroDとの相互作用が亢進する (2016)
  • Author(s): 韓松伊、常陰幸乃、片岡浩介
  • Organizer: 第39回日本分子生物学学会年会
  • Place of Presentation: パシフィコ横浜 神奈川県横浜市
  • Year and Date: 2016-11-30