Novel drug discovery for dislipidemia

• Project/Area Number: 17K19766
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Oral Science and related fields
• Research Institution: Fukuoka Dental College
• Principal Investigator: Hirata Masato 福岡歯科大学, 口腔歯学部, 客員教授 (60136471)
• Project Period (FY): 2017-06-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: オステオカルシン / 脂肪酸ベータ酸化 / 脂質異常症 / フィブラート製剤 / 脂肪酸β酸化 / シグナル伝達 / 生理活性

Outline of Final Research Achievements

Deletion of GPRC6A resulted in the reduction of some metabolic enzymes located in mitochondria and peroxisomes in vitro. Furthermore, the fact that membrane proteins on mitochondria and peroxisomes are also decreased, implying GPRC6A plays pivotal roles in energy metabolism via the regulation of organelle homeostasis.

Academic Significance and Societal Importance of the Research Achievements

細胞機能の発現は、その細胞内に存在するオルガネラに依存するところが大きい。今回、GPRC6Aがエネルギー代謝で最も重要なオルガネラであるミトコンドリアのホメオスタシスに関与していることを細胞レベルで見出した。この点は、細胞生物学的な観点からはもちろんのこと、メタボリックシンドロームの改善という医学的な観点からも非常に重要な知見である。すなわち、本研究成果はGPRC6Aを標的としてミトコンドリア増殖の亢進（エネルギー代謝促進、白色脂肪細胞の褐色脂肪細胞化など）やがん細胞におけるワールブルク効果を消滅させ、アポトーシスの惹起を実現させる可能性を秘めている。

Research Products

• [Journal Article] Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis (2021)
  • Author(s): Mukai Satoru、Mizokami Akiko、Otani Takahito、Sano Tomomi、Matsuda Miho、Chishaki Sakura、Gao Jing、Kawakubo-Yasukochi Tomoyo、Tang Ronghao、Kanematsu Takashi、Takeuchi Hiroshi、Jimi Eijiro、Hirata Masato
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100274-100274
  • DOI: 10.1016/j.jbc.2021.100274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NFAT5 promotes oral squamous cell carcinoma progression in a hyperosmotic environment (2020)
  • Author(s): Yoshimoto Shohei、Morita Hiromitsu、Matsuda Miho、Katakura Yoshinori、Hirata Masato、Hashimoto Shuichi
  • Journal Title: Laboratory Investigation Volume: 101 Issue: 1 Pages: 38-50
  • DOI: 10.1038/s41374-020-00486-1
  • Peer Reviewed / Open Access
• [Journal Article] The roles of osteocalcin in lipid metabolism in adipose tissue and liver (2020)
  • Author(s): Otani Takahito、Mizokami Akiko、Kawakubo-Yasukochi Tomoyo、Takeuchi Hiroshi、Inai Tetsuichiro、Hirata Masato
  • Journal Title: Advances in Biological Regulation Volume: 78 Pages: 100752-100752
  • DOI: 10.1016/j.jbior.2020.100752
  • Peer Reviewed / Open Access
• [Journal Article] GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J. Endocrinol. (2020)
  • Author(s): Mizokami, A., Mukai, S., Gao, J., Kawakubo-Yasukochi, T., Otani, T., Takeuchi, H., Jimi, E., Hirata, M.
  • Journal Title: Journal of Endocrinology Volume: 244 Issue: 2 Pages: 285-296
  • DOI: 10.1530/joe-19-0288
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice (2019)
  • Author(s): Yamawaki Yosuke、Shirawachi Satomi、Mizokami Akiko、Nozaki Kanako、Ito Hikaru、Asano Satoshi、Oue Kana、Aizawa Hidenori、Yamawaki Shigeto、Hirata Masato、Kanematsu Takashi
  • Journal Title: Neurochemistry International Volume: 131 Pages: 104563-104563
  • DOI: 10.1016/j.neuint.2019.104563
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein regulates cytokinesis by protecting phosphatidylinositol 4,5-bisphosphate from metabolism in the cleavage furrow (2019)
  • Author(s): Asano, S., Ikura, Y., Nishimoto, M., Yamawaki, Y., Hamao, K., Kamijo, K., Hirata, M. and Kanematsu, T.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12729-12729
  • DOI: 10.1038/s41598-019-49156-3
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice (2019)
  • Author(s): Furukawa Tomonori、Nikaido Yoshikazu、Shimoyama Shuji、Ogata Yoshiki、Kushikata Tetsuya、Hirota Kazuyoshi、Kanematsu Takashi、Hirata Masato、Ueno Shinya
  • Journal Title: Journal of Anesthesia Volume: 33 Issue: 4 Pages: 531-542
  • DOI: 10.1007/s00540-019-02663-z
  • NAID: 40021971791
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein: A novel signaling molecule for modulating fat metabolism and energy expenditure (2019)
  • Author(s): Kanematsu T, Oue K, Okumura T, Harada K, Yamawaki Y, Asano S, Mizokami A, Irifune M, Hirata M
  • Journal Title: J Oral Biosci Volume: 61(2) Issue: 2 Pages: 65-72
  • DOI: 10.1016/j.job.2019.04.002
  • Peer Reviewed / Open Access
• [Journal Article] Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes regulated by the activation of p300. (2018)
  • Author(s): Otani, T., Matsuda, M., Mizokami, A., Kitagawa, N., Takeuchi, H., Jimi, E.,Inai, T., and Hirata, M.
  • Journal Title: Cell Death Disease Volume: 9 Issue: 12 Pages: 1194-1210
  • DOI: 10.1038/s41419-018-1257-7
  • Peer Reviewed / Open Access
• [Journal Article] Poor motor-function recovery after spinal-cord injury in anxiety-model mice with phospholipase related catalytically inactive protein type 1 knockout. (2018)
  • Author(s): Taka Fujita, Gentaro Kumagai, Xizhe Liu, Kanichiro Wada, Toshihiro Tanaka, Hitoshi Kudo, Toru Asari, Tatsuhiro Fukutoku, Ayako Sasaki, Yohshiro Nitobe, Yoshikazu Nikaido, Ken-Ichi Furukawa, Masato Hirata, Takashi Kanematsu, Shinya Ueno, Yasuyuki Ishibash
  • Journal Title: Journal of Neurotrauma Volume: 印刷中 Issue: 12 Pages: 1379-1386
  • DOI: 10.1089/neu.2017.5492
  • Peer Reviewed / Open Access
• [Journal Article] 骨による全身の糖・エネルギー代謝調節機構 (2018)
  • Author(s): 溝上 顕子、平田 雅人
  • Journal Title: FOOD Style 21 Volume: 22 Pages: 50-53
• [Journal Article] Phospholipase C-related, but catalytically inactive protein (PRIP) up-regulates osteoclast differentiation via calcium-calcineurin-NFATc1 signaling. (2017)
  • Author(s): Murakami, A., Matsuda, M., Harada, Y., Hirata, M.
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 19 Pages: 7994-8006
  • DOI: 10.1074/jbc.m117.784777
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related but catalytically inactive proteins regulate ovarian follicle development. (2017)
  • Author(s): Matsuda, M., Hirata, M.
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 20 Pages: 8369-8380
  • DOI: 10.1074/jbc.m116.759928
  • Peer Reviewed / Open Access
• [Journal Article] Propofol anesthesia is reduced in Phospholipase C-related inactive protein type-1 knockout mice (2017)
  • Author(s): Nikaido Y, Furukawa T, Shimoyama S, Yamada J, Migita K, Koga K, Kushikata T, Hirota K, Kanematsu T, Hirata M, Ueno S
  • Journal Title: The Journal of pharmacology and experimental therapeutics Volume: 361(3) Issue: 3 Pages: 367-374
  • DOI: 10.1124/jpet.116.239145
  • Peer Reviewed / Open Access
• [Journal Article] Uncarboxylated osteocalcin induces antitumor immunity against mouse melanoma cell growth. (2017)
  • Author(s): Hayashi Y, Kawakubo-Yasukochi T, Mizokami A, Hazekawa M, Yakura T, Naito M, Takeuchi H, Nakamura S, Hirata M.
  • Journal Title: J Cancer Volume: 8 Issue: 13 Pages: 2478-2486
  • DOI: 10.7150/jca.18648
  • NAID: 120006900041
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling (2017)
  • Author(s): Asano Satoshi、Taniguchi Yuri、Yamawaki Yosuke、Gao Jing、Harada Kae、Takeuchi Hiroshi、Hirata Masato、Kanematsu Takashi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 5408-5408
  • DOI: 10.1038/s41598-017-05908-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 歯学研究の多様性 (2020)
  • Author(s): 平田雅人
  • Organizer: 第６２回歯科基礎医学会
• [Presentation] オステオカルシンが制御する胎内栄養環境応答と疾病素因形成 (2020)
  • Author(s): 安河内（川久保）友世、溝上顕子、平田雅人
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 骨基質タンパク質オステオカルシンが PC12 の細胞増殖と神経様細胞分化に及ぼす影響 (2020)
  • Author(s): 安藤瑛香、東泉、溝上顕子、大住伴子、渡邉誠之、平田雅人、竹内弘
  • Organizer: 第93回日本薬理学会年会
• [Presentation] シグナル分子PRIPは卵胞成熟制御に関与する (2019)
  • Author(s): 松田美穂、自見英治郎、平田雅人
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 脂肪細胞におけるGPRC6Aシグナリングの生理的意義 (2019)
  • Author(s): 向井 悟、溝上顕子、大谷崇仁、松田美穂、竹内 弘、自見英治郎、平田雅人
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] オステオカルシンの代謝改善効果におけるGLP-1受容体シグナルの役割 (2019)
  • Author(s): 溝上顕子、向井 悟、竹内 弘、自見英治郎、平田雅人
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] Serendipityを求めて (2019)
  • Author(s): 平田雅人
  • Organizer: 第61回歯科基礎医学会学術大会
  • Invited
• [Presentation] 脂肪細胞を細胞死へと導く骨基質タンパク質Osteocalcin (2019)
  • Author(s): 大谷崇仁、松田美穂、溝上顕子、北河憲雄、自見英治郎、稲井哲一朗、平田雅人
  • Organizer: 第61回歯科基礎医学会学術大会
  • Invited
• [Presentation] The effect of maternal uncarboxylated osteocalcin on the metabolic properties of next generation (2019)
  • Author(s): Kawakubo-Yasukochi, T., Kondo, A., Mizokami, A. and Hirata, M.
  • Organizer: DOHaD World Congress 2019
  • Int'l Joint Research
• [Presentation] Oral administration of osteocalcin, bone-derived hormone, improves the performance of voluntary exercise concomitant with the amelioration of fat utilization in mice (2019)
  • Author(s): Tajiri, Y., Sakai, Y., Mifune, H and Hirata, M.
  • Organizer: The 55th Annual Meeting of the European Association for the Study of Diabetes (EASD)
  • Int'l Joint Research / Invited
• [Presentation] Adipocyte-specific GPRC6A ablation induces diet-induced obesity by inhibiting lipolysis (2019)
  • Author(s): Mizokami, A., Mukai, S., Otani, T., Takeuchi, H., Jimi, E. and Hirata, M.
  • Organizer: 2019 International Conference on Obesity and Metabolic Syndrome
  • Int'l Joint Research / Invited
• [Presentation] Glucagon-like peptide-1 receptor signaling is required for an osteocalcin-mediated improvement of glucose tolerance (2019)
  • Author(s): Mizokami, A. and Hirata, M.
  • Organizer: American Diabetes Association (ADA) 79th Scientific Sessions
  • Int'l Joint Research
• [Presentation] 骨は内分泌器官 (2019)
  • Author(s): 平田雅人
  • Organizer: 第73回日本口腔科学会大会
  • Invited
• [Presentation] 脂肪細胞表面受容体GPRC6Aを介した脂肪蓄積機構 (2018)
  • Author(s): 溝上 顕子、松田 美穂、竹内 弘、安河内友世、自見英治郎、平田 雅人
  • Organizer: 第60回歯科基礎医学会学術大会
  • Invited
• [Presentation] Programmed necrosis of adipocytes induced by high-dose osteocalcin (2018)
  • Author(s): Otani T, Hirata M, Mizokami A, Kitagawa N, Jimi E. and Inai T.
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] Induction of necroptosis in adipocytes by osteocalcin (2018)
  • Author(s): 大谷 崇仁、溝上 顕子、北河 憲雄、松田 美穂、自見英治郎、稲井哲一朗、平田 雅人
  • Organizer: 第91回日本生化学会大会
• [Presentation] 妊娠母体が摂取したオステオカルシンが次世代に及ぼす影響 (2017)
  • Author(s): 川久保-安河内友世、近藤皓彦、溝上顕子、平田雅人
  • Organizer: 第6回日本DOHaD学会学術集会
• [Presentation] Sex differences in the regulation of energy metabolism by osteocalcin (2017)
  • Author(s): Mizokami, A., Kawakubo-Yasukochi, T. and Hirata, M.
  • Organizer: 2017 International Conference on Obesity and Metabolic Syndrome
  • Int'l Joint Research / Invited
• [Presentation] 脂肪細胞特異的GPRC6A欠損が全身代謝に与える影響 (2017)
  • Author(s): 溝上顕子、竹内 弘、自見英治郎、平田雅人
  • Organizer: 第59回歯科基礎医学会学術大会
• [Presentation] シグナル調節分子PRIPの破骨細胞分化における役割 (2017)
  • Author(s): 松田美穂、自見英治郎、平田雅人
  • Organizer: 第59回歯科基礎医学会学術大会
• [Presentation] 動脈硬化の病態におけるオステオカルシンの役割 (2017)
  • Author(s): 近藤皓彦、川久保-安河内友世、溝上顕子、自見英治郎、平田雅人
  • Organizer: 第59回歯科基礎医学会学術大会
• [Presentation] オステオカルシンによる脂肪細胞へのネクロトーシス誘導メカニズムの解明 (2017)
  • Author(s): 大谷崇仁、溝上顕子、北河憲雄、稲井哲一朗、平田雅人
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] 脂肪組織特異的GPRC6A欠損マウスの作製とその脂質代謝異常の解析 (2017)
  • Author(s): 向井悟、溝上顕子、樗木さくら、松田美穂、竹内弘、大谷崇仁、自見英治郎、平田雅人
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] インスリン受容体基質のリン酸化制御におけるPRIPの役割 (2017)
  • Author(s): 高靖、溝上顕子、竹内弘、自見英治郎、平田雅人
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] シグナル分子PRIPのカルシウムを介した破骨細胞分化制御への関わり (2017)
  • Author(s): 松田美穂、村上絢子、自見英治郎、平田雅人
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Patent(Industrial Property Rights)] 自発運動増強用組成物 (2019)
  • Inventor(s): 学校法人久留米大学、平田雅人
  • Industrial Property Rights Holder: 学校法人久留米大学、平田雅人
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-167223
  • Filing Date: 2019