生理活性脂質リゾホスファチジン酸による血管新生・細胞浸潤・転移制御とその意義

• Project/Area Number: 18013018
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University (2007); The University of Tokyo (2006)
• Principal Investigator: 青木 淳賢 Tohoku University, 大学院・薬学研究科, 教授 (20250219)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥12,800,000 (Direct Cost: ¥12,800,000); Fiscal Year 2007: ¥6,500,000 (Direct Cost: ¥6,500,000); Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000)
• Keywords: リゾホスファチジン酸 / オートタキシン / 血管新生 / がん

Research Abstract

リゾホスファチジン酸(LPA)は、in vitroで細胞増殖、細胞運動性の亢進など多彩な機能を発揮するユニークな生理活性脂質である。LPAの作用は、G蛋白質共役型受容体を介することが知られており、近年、LPA受容体ノックアウトマウスを用いた解析から、LPAが脳神経系の発達や生殖系の発育に必須であることが明らかになってきた。LPAは血清中に多く含まれていることが知られているが、本研究者はこれまで血清中のLPA産生経路を解析し、血清LPAは様々な経路で産生されることを明らかにしてきた。また、血清中の主要なLPA産生酵素リゾホスホリパーゼD(lysoPLD)の同定を行った。lysoPLDは血中に数百μMと高濃度で存在するリゾホスファチジルコリン(LPC)をLPAに変換する酵素であり、本酵素を精製した結果、1ysoPLDは癌細胞運動性促進因子であるautotaxinと同一であることがわかった。また、昨年度、autotaxin/1ysoPLDノックアウト(KO)マウスの解析を行い、KOマウスが胚致死であること、autotaxin/1ysoPLDヘテロマウスは1ysoPLD活性やLPAレベルが野生型の半分になるにもかかわらずほとんど表現型を示さないことを明らかにした。今年度は、autotaxin/lysoPLDの成体での役割を明らかにするためにautotaxin/1ysoPLDの機能を阻害するモノクローナル抗体の単離を試みた。マウスautotaxin/1ysoPLDをラットに免疫し、数十の抗autotaxin/1ysoPLDモノクローナル抗体を得た。このうち幾つかのクローンは個体レベルでautotaxin/lysoPLDの活性を落とすことが明らかとなった。

Research Products

• [Journal Article] Protection against oxidative stress-induced hepatic injury by intracellular type II PAF-acetylhydrolase by metabolism of oxidized phospholipids in vivo. (2008)
  • Author(s): Kono N, Inoue T, Yoshida Y, Sato H, Matsusue T, Itabe H, Niki E, Aoki J, Arai H.
  • Journal Title: J. Biol. Chem. 283 Pages: 1628-1636
  • Peer Reviewed
• [Journal Article] Analysis of serum and urinary lysophospholipase D/autotaxin in nephrotic syndrome. (2008)
  • Author(s): Nakamura K, Nangaku M, Ohkawa R, Okubo S, Yokota H, Ikeda H, Aoki J, Yatomi Y.
  • Journal Title: Clin. Chem. Lab. Med. 46 Pages: 150-151
  • Peer Reviewed
• [Journal Article] Validation of an autotaxin enzyme immunoassay in human serum samples and its application to hypoalbuminemia differentiation. (2008)
  • Author(s): Nakamura K, Igarashi K, Ide K, Ohkawa R, Okubo S, Yokota H, Masuda A, Oshima N, Takeuchi T, Nangaku M, Okudaira S, Arai H, Ikeda H. Aoki J, Yatomi Y.
  • Journal Title: Clin. Chim. Acta 388 Pages: 51-58
  • Peer Reviewed
• [Journal Article] Embryo Spacing and Implantation Timing Are Differentially Regulated by LPA3-Mediated Lysophosphatidic Acid Signaling in Mice. (2007)
  • Author(s): Hama K, Aoki J, Inoue A, Endo T, Amano T, Motoki R, Kanai M, YeX, Chun J, Matsuki N, Suzuki H, Shibasaki M, Arai H.
  • Journal Title: Biol. Reprod. 77 Pages: 954-959
  • Peer Reviewed
• [Journal Article] Phospholipase A (1) assays using a radiolabeled substrate and mass spectrometry. (2007)
  • Author(s): Morikawa R, Tsujimoto M, Arai H, Aoki J.
  • Journal Title: Methods Enzymol. 434 Pages: 1-13
  • Peer Reviewed
• [Journal Article] Serum lysophospholipase D/autotaxin may be a new nutritional assessment marker: study on prostate cancer patients. (2007)
  • Author(s): Nakamura K, Takeuchi T, Ohkawa R, Okubo S, Yokota H, Tozuka M, Aoki J, Arai H, Ikeda H, Ohshima N, Kitamura T, Yatomi Y.
  • Journal Title: Ann. Clin. Biochem. 44 Pages: 549-556
  • Peer Reviewed
• [Journal Article] Type I platelet-activating factor acetylhydrolase catalytic subunits over-expression induces pleiomorphic nuclei and centrosome amplification. (2007)
  • Author(s): Yamaguchi N, Koizumi H, Aoki J, Natori Y, Nishikawa K, Natori Y, Takanezawa Y, Arai H.
  • Journal Title: Genes Cells 12 Pages: 1153-1161
  • Peer Reviewed
• [Journal Article] Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity. (2007)
  • Author(s): Watanabe N, Ikeda H, Nakamura K, Ohkawa R, Kume Y, Tomiya T, Tejima K, Nishikawa T, Arai M, Yanase M, Aoki J, Arai H, Omata M, Fujiwara K, Yatomi Y.
  • Journal Title: Life Sci. 81 Pages: 1009-1015
  • Peer Reviewed
• [Journal Article] Submucosal connective tissue-type mast cells contribute to the production of lysophosphatidic acid (LPA) in the gastrointestinal tract through the secretion of autotaxin (ATX)/lysophospholipase D (lysoPLD). (2007)
  • Author(s): Mori K, Kitayama J, Aoki J, Kishi Y, Shida D, Yamashita H, Arai H, Nagawa H.
  • Journal Title: Virchows Arch. 451 Pages: 47-56
  • Peer Reviewed
• [Journal Article] Lysophosphatidic acid protection against apoptosis in the human pre-B-cell line Nalm-6. (2007)
  • Author(s): Satoh Y, Ohkawa R, Nakamura K, Higashi K, Kaneko M, Yokota H, Aoki J, Arai H, Yuasa Y, Yatomi Y.
  • Journal Title: Eur. J. Haematol. 78 Pages: 510-517
  • Peer Reviewed
• [Journal Article] Diversified expression patterns of autotaxin, gene for phospholipid-generating enzyme during mouse and chicken development. (2007)
  • Author(s): Ohuchi H, Hayashibara Y, Matsuda H, Onoi M, Mitsumori M, Tanaka M, Aoki J, Arai H, Noji S.
  • Journal Title: Dev. Dyn. 236 Pages: 1134-1143
  • Peer Reviewed
• [Journal Article] Peritoneal fluids from patients with certain gynecologic tumor contain elevated levels of bioactive lysophospholipase D activity. (2007)
  • Author(s): Tokumura A, Kume T, Fukuzawa K, Tahara M, Tasaka K, Aoki J, Arai H
  • Journal Title: Life Sci. 80 Pages: 1641-1649
  • Peer Reviewed
• [Journal Article] Neuroprotective Role of Transgenic PAF-Acetylhydrolase II in Mouse Models of Focal Cerebral Ischemia. (2007)
  • Author(s): Umemura K, Kato I, Hirashima Y, Ishii Y, Inoue T, Aoki J, Kono N, Oya T, Hayashi N, Hamada H, Endo S, Oda M, Arai H, Kinouchi H, Hiraga K.
  • Journal Title: Stroke 38 Pages: 1036-1068
  • Peer Reviewed
• [Journal Article] Plasma lysophosphatidic acid is increased in liver fibrosis in rats and human with enhanced serum autotaxin level. (2007)
  • Author(s): Watanabe N, Ikeda H, Nakamura K, Ohkawa R, Kume Y, Aoki J, Hama K, Okudaira S, Tanaka M, Yanase M, Nagashima K, Tomiya T, Arai M, Inoue Y, Tejima K, Nishikawa T, Arai H, Omata M, Fujiwara K, Yatomi Y
  • Journal Title: J. Clin. Gastroenterol 41 Pages: 616-623
  • Peer Reviewed
• [Journal Article] Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family (review). (2007)
  • Author(s): Aoki J, Inoue A, Makide K, Saiki N, Arai H.
  • Journal Title: Biochimie 89 Pages: 197-204
  • Peer Reviewed
• [Journal Article] Measurement of lysophospholipase D/autotaxin activity in human serum samples (2007)
  • Author(s): Nakamura K, Ohkawa R, Okubo S, Tozuka M, Okada M, Aoki S, Aoki J, Arai H, Ikeda H, Yatomi Y
  • Journal Title: Clin. Biochem. 40 Pages: 274-277
  • Peer Reviewed
• [Journal Article] Autotaxin (NPP-2) in the brain: Cell type-specific expression and regulation during development and after neurotrauma (2007)
  • Author(s): Savaskan NE, Rocha L, Kotter MR, Lubec G, Baer A, van Meeteren LA, Kishi Y, Aoki J, Moolenaar WH, Nitsch R, Brauer AU.
  • Journal Title: Cell. Mol. Life Sci. 64 Pages: 230-243
  • Peer Reviewed
• [Journal Article] Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid (2006)
  • Author(s): H.Sakagami et al.
  • Journal Title: J. Biol. Chem. 281 Pages: 25822-25830
• [Journal Article] Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcoholine to lysophosphatidic acid (2006)
  • Author(s): Y.Kishi et al.
  • Journal Title: J. Biol. Chem. 281 Pages: 17492-17500
• [Journal Article] Cyclic phosphatidic acid is produced by autotaxin in blood (2006)
  • Author(s): S.Tsuda et al.
  • Journal Title: J Biol. Chem. 201 Pages: 26081-26088
• [Journal Article] Phospholipase A1 -structure, distribution and function- (2006)
  • Author(s): A.Inoue at al.
  • Journal Title: Future Lipidology 1 Pages: 687-700
• [Journal Article] Lysophosphatidic receptor, LPA3, is positively and negatively regulated by progesterone and estrogen in the mouse uterus (2006)
  • Author(s): K.Hama et al.
  • Journal Title: Life Sciences 79 Pages: 736-1740
• [Journal Article] Transgenic Expression of Group V, but not Group X, Secreted PLA2 in Mice Leads to Neonatal Lethality due to Lung Dysfunction (2006)
  • Author(s): M.Ohtsuki et al.
  • Journal Title: J. Biol. Chem. 281 Pages: 36420-36433