Biological regulation by Galpha12/13-mediated lipid mediator function

• Project/Area Number: 16H05136
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Akita University
• Principal Investigator: Satoshi Ishii 秋田大学, 医学系研究科, 教授 (10300815)
• Co-Investigator(Kenkyū-buntansha): 丸山 貴司 秋田大学, 医学系研究科, 准教授 (10622524) ; 安田 大恭 秋田大学, 医学系研究科, 助教 (70594951) ; 赤星 軌征 昭和薬科大学, 薬学部, 講師 (70534551) ; 大戸 貴代 秋田大学, 医学(系)研究科(研究院), 助教 (80511378)
• 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: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: シグナル伝達 / LPA / リゾフォスファチジン酸 / 脂質

Outline of Final Research Achievements

We revealed that adipogenesis and adipocyte function are regulated by LPA4, a fourth subtype of G-protein coupled receptor for lysophosphatidic acid (LPA). In brief, LPA4-knockout mice showed enhanced expression of adipogenesis genes and reduced level of inhibitory phosphorylation of PPARγ in white adipose tissue, along with increased production of adiponectin. In mouse embryonic fibroblast-derived adipocytes, LPA4 activation consistently suppressed the mRNA expression of adipogenesis genes and also genes regulated by the phosphorylation of PPARγ in a G12/13 protein-dependent manner. LPA4 signaling seems to limit proper remodeling of white adipose tissue in diet-induced obesity.

Academic Significance and Societal Importance of the Research Achievements

LPA4シグナルによる白色脂肪細胞の分化や機能の抑制は、白色脂肪組織が多量の脂肪を蓄積するときに起きる過度なリモデリングとそれに伴う組織の慢性炎症の原因となる。今後LPA4について、KOマウスのさらなる解析に加えて選択的アゴニストやアンタゴニストの開発が進めば、肥満に伴うインスリン抵抗性（2型糖尿病）に対する新しい治療法の創出につながることが期待される。

Research Products

• [Int'l Joint Research] Academia Sinica/National Central University(台湾)
• [Journal Article] Molecular mechanism of lysophosphatidic acid-induced hypertensive response (2019)
  • Author(s): Kano, K., Matsumoto, H., Inoue, A., Yukiura, H., Kanai, M., Chun, J., Ishii, S., Shimizu, T., and Aoki, J.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 2662-2662
  • DOI: 10.1038/s41598-019-39041-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-EDG family LPA receptors (2018)
  • Author(s): 石井 聡、柳田 圭介
  • Journal Title: 生化学 Volume: 90 Issue: 5 Pages: 596-608
  • DOI: 10.14952/SEIKAGAKU.2018.900596
  • ISSN: 0037-1017
  • Year and Date: 2018-10-25
• [Journal Article] The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity (2018)
  • Author(s): Yanagida Keisuke、Igarashi Hidemitsu、Yasuda Daisuke、Kobayashi Daiki、Ohto-Nakanishi Takayo、Akahoshi Noriyuki、Sekiba Atsushi、Toyoda Tsudoi、Ishijima Tomoko、Nakai Yuji、Shojima Nobuhiro、Kubota Naoto、Abe Keiko、Kadowaki Takashi、Ishii Satoshi、Shimizu Takao
  • Journal Title: JCI Insight Volume: 3 Issue: 24 Pages: 397293-397293
  • DOI: 10.1172/jci.insight.97293
  • Peer Reviewed / Open Access
• [Journal Article] リゾホスファチジン酸（LPA）を 介した骨髄ニッチの制御 (2018)
  • Author(s): 石井聡、五十嵐秀光
  • Journal Title: 臨床免疫・アレルギー科 Volume: 70 Pages: 221-228
• [Journal Article] LPA5 signaling is involved in multiple sclerosis-mediated neuropathic pain in the cuprizone mouse model (2018)
  • Author(s): Tsukahara Ryoko、Yamamoto Shinji、Yoshikawa Keisuke、Gotoh Mari、Tsukahara Tamotsu、Neyama Hiroyuki、Ishii Satoshi、Akahoshi Noriyuki、Yanagida Keisuke、Sumida Hayakazu、Araki Masatake、Araki Kimi、Yamamura Ken-ichi、Murakami-Murofushi Kimiko、Ueda Hiroshi
  • Journal Title: Journal of Pharmacological Sciences Volume: 136 Issue: 2 Pages: 93-96
  • DOI: 10.1016/j.jphs.2018.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Lysophosphatidic acid receptor 4 activation augments drug delivery in tumors by tightening endothelial cell-cell contact. (2017)
  • Author(s): Takara K., Eino D., Ando K., Yasuda D., Naito H., Tsukada Y., Iba T., Wakabayashi T., Muramatsu F., Kidoya H., Fukuhara S., Mochizuki N., Ishii S., Kishima H., Takakura N.
  • Journal Title: Cell Reports Volume: 20 Issue: 9 Pages: 2072-2086
  • DOI: 10.1016/j.celrep.2017.07.080
  • Peer Reviewed / Open Access
• [Journal Article] Identification of optineurin as an interleukin-1 receptor-associated kinase 1-binding protein and its role in regulation of MyD88-dependent signaling (2017)
  • Author(s): Tanishima, M., Takashima, S., Honda, A., Yasuda, D., Tanikawa, T., Ishii, S., and MaruYama, T.
  • Journal Title: J. Biol. Chem. Volume: 292 Issue: 42 Pages: 17250-17257
  • DOI: 10.1074/jbc.m117.813899
  • Peer Reviewed
• [Journal Article] Involvement of TRPV1 and TDAG8 in pruriception associated with noxious acidosis (2017)
  • Author(s): Lin, S.-H., Steinhoff, M., Ikoma, A., Chang, Y.-C., Cheng, Y.-R., Kopparaju, R.C., Ishii, S., Sun, W.-H., and Chen, C.-C.
  • Journal Title: J. Invest. Dermatol. Volume: 137 Issue: 1 Pages: 170-178
  • DOI: 10.1016/j.jid.2016.07.037
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice (2017)
  • Author(s): Dai, S.-P., Huang, Y.-H., Chang, C.-J., Huang, Y.-F., Hsieh, W.-S., Tabata, Y., Ishii, S., and Sun, W.-H.
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 41415-41415
  • DOI: 10.1038/srep41415
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes. (2016)
  • Author(s): Hata E, Sasaki N, Takeda A, Tohya K, Umemoto E, Akahoshi N, Ishii S, Bando K, Abe T, Kano K, Aoki J, Hayasaka H, Miyasaka M
  • Journal Title: Int Immunol. Volume: なし Issue: 6 Pages: 283-292
  • DOI: 10.1093/intimm/dxv072
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Blood-brain barrier permeability of ginkgolide: Comparison of the behavior of PET probes 7a-[18F]fluoro- and 10-O-p-[11C]methylbenzyl ginkgolide B in monkey and rat brains. (2016)
  • Author(s): Doi, H., Sato, K., Shindou, H., Sumi, K., Koyama, H., Hosoya, T., Watanabe, Y., Ishii, S., Tsukada, H., Nakanishi, K., and Suzuki, M.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 21 Pages: 5148-5157
  • DOI: 10.1016/j.bmc.2016.08.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] リゾホスファチジン酸受容体LPA4の脂肪細胞における機能 (2018)
  • Author(s): 柳田圭介、安田大恭、小林大礎、清水孝雄、石井聡
  • Organizer: 第91回日本生化学会大会
• [Presentation] LPA5による接触性皮膚炎の制御 (2018)
  • Author(s): 丸山貴司、石井聡
  • Organizer: 第60回日本脂質生化学会
• [Presentation] Gα12/13-coupled LPA receptors mediate novel angiogenesis mechanism (2017)
  • Author(s): Daisuke Yasuda and Satoshi Ishii
  • Organizer: ASEB Summer Research Conferences; Lysophospholipid and Related Mediators: From Bench to Clinic
  • Int'l Joint Research
• [Presentation] リゾホスファチジン酸による血管新生調節機序 (2017)
  • Author(s): 安田大恭, 石井 聡
  • Organizer: 第59回日本脂質生化学会大会
• [Presentation] リゾホスファチジン酸受容体LPA5を介したT細胞の分化運命決定機構 (2017)
  • Author(s): 丸山貴司, 大戸貴代, 石井 聡
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] Gα12/13共役型リゾホスファチジン酸受容体が調節する血管新生の分子機構 (2017)
  • Author(s): 安田大恭, 石井 聡
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] 三量体型Ｇタンパク質Ｇα12/13を介した脂質メディエーターによる生体制御 (2016)
  • Author(s): 石井聡
  • Organizer: 第81回秋田県医学会総会
  • Place of Presentation: 秋田県総合保健センター
  • Year and Date: 2016-11-23
  • Invited
• [Presentation] リゾホスファチジン酸（LPA）受容体の細胞分化制御機能 (2016)
  • Author(s): 石井聡
  • Organizer: 日本脂質栄養学会 第25回大会
  • Place of Presentation: 秋田市にぎわい交流館あう
  • Year and Date: 2016-09-17
  • Invited
• [Remarks] プレス発表資料
  • URL: http://rproxy.akita-u.ac.jp/honbu/event/img/pro30742_01_dl.pdf