Biological and pharmaceutical study on intracellular lipid droplets which are the key organelle to understand life style diseases.

• Project/Area Number: 19590076
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Showa University
• Principal Investigator: ITABE Hiroyuki Showa University, 薬学部, 教授 (30203079)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Katsuhiko 昭和薬科大学, 准教授 (80307066) ; KATO Rina 昭和大学, 薬学部, 助教 (30392400) ; OBAMA Takashi 昭和大学, 薬学部, 助教 (60395647)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 細胞内脂肪滴 / ADRP / 脂肪酸 / グルカゴン / Aキナーゼ / トリグリセリド / 脂肪肝 / メタボリックシンドローム / 生活習慣病 / 肝細胞 / アディポフィリン / 非アルコール性脂肪肝炎

Research Abstract

生活習慣病の要因である肥満や高脂血症は、脂質代謝異常に起因する。脂質代謝の基盤として注目されている細胞内脂肪滴は、種々細胞に普遍的に存在し脂質の蓄積と利用を担う構造体である。絶食により一過的に脂肪蓄積が亢進するマウス肝で、脂肪滴局在タンパク質のADRPが顕著に誘導され、そのADRPは通常の脂肪滴や膜画分とは異なる中間比重画分に分布することを見出した。培養肝細胞HuH-7に脂肪酸を添加すると、ADRPが誘導され脂肪滴が生成するが中間比重脂肪滴は生じない。一方、グルカゴン刺激すると中間比重脂肪滴が出現した。この反応はジブチリルcAMPで再現され、Aキナーゼ阻害剤によって抑制されたことから、肝細胞内脂肪滴形成を伴う脂肪蓄積に、グルカゴン刺激によるcAMP依存性の調節機構が存在することが示された。

Research Products

• [Journal Article] Docosahexaenoic acid induces adipose differentiation-related protein through activation of retinoid X receptor in human choriocarcinoma BeWo cells (2009)
  • Author(s): Suzuk K, Takahashi K, Nishimaki-Mogami T, Kagechika H, Yamamoto M, and Itabe H.
  • Journal Title: Biol. Pharm. Bull (In press)
  • NAID: 130000117213
• [Journal Article] Transient increase in plasma oxidized LDL during the progression of atherosclerosis in apolipoprotein E knockout mice (2009)
  • Author(s): Kato R, Mori C, Kitazato K, Arata S, Obama T, Mori M, Takahashi K, Aiuchi T, Takano T, and Itabe H.
  • Journal Title: Arterioscler Thromb Vasc Biol 29(1) Pages: 33-39
• [Journal Article] Transient increase in plasma oxidized LDL during the progression of atherosclerosis in apolipoprotein E knockout mice. (2009)
  • Author(s): Kato R, Mori C, Kitazato K, Arata S, Obama T, Mori M, Takahashi K, Aiuchi T, Takano T, Itabe H.
  • Journal Title: Arterioscler Thromb Vasc Biol. 29 Pages: 33-39
  • Peer Reviewed
• [Journal Article] IFN-g down-regulates secretoglobin 3A1 gene expression. (2009)
  • Author(s): Yamada A. Suzuki D, Miyazono A, Oshima K, Kamiya A, Zhao B, Takami M, Donnelly RP, Itabe H, Yamamoto M, Kimura S, Kamijo R.
  • Journal Title: Biochem. Biophys. Res. Commun. 379 Pages: 964-968
  • Peer Reviewed
• [Journal Article] Mechanism of inhibition of tumor angiogenesis by β-hydroxyisovalerylshikonin. (2009)
  • Author(s): Komi Y, Suzuki Y, Shimamura M, Kajimoto S, Nakajo S, Masuda M, Shibuya M, Itabe H, Shimokado K, Oettgen P, Nakaya K, Kojima S.
  • Journal Title: Cancer Science 100 Pages: 269-277
  • NAID: 10025142358
  • Peer Reviewed
• [Journal Article] Chronic urotensin II infusion enhances macrophage foam cell formation and atherosclerosis in apolipoprotein E-knockout mice (2008)
  • Author(s): Shiraishi Y, Watanabe T, Suguro T, Nagashima M, Kato R, Hongo S, Itabe H, Miyazaki A, Hirano T, Adachi M.
  • Journal Title: J. Hypertens 26(10) Pages: 1955-1965
• [Journal Article] Analyses of group III secreted phospholipase A2 transgenic mice reveals potential participation of this enzyme in plasma lipoprotein modification (2008)
  • Author(s): Sato H, Kato R, Isogai Y, Saka G, Ohtsuki M, Taketomi Y, Yamamoto K, Tsutsumi K, Yamada J, Masuda S, Ishikawa Y, Ishii T, Kobayashi T, Ikeda K, Taguchi R, Hatakeyama S, Hara S, Kudo I, Itabe H, and Murakami M.
  • Journal Title: macrophage foam cell Formation, and atherosclerosis. J. Biol. Chem. 283(48) Pages: 33483-33497
• [Journal Article] Plasma levels of oxidized low density lipoprotein are associated with stable angina pectoris and modalities of acute coronary syndrome. (2008)
  • Author(s): Imazu M, Ono K, Tadehara F, Kajiwara K, Yamamoto H, Sumii K, Tasaki N, Oiwa J, Shimohara Y, Gomyo Y, Itabe H.
  • Journal Title: Int. Heart J. 49 Pages: 515-524
  • NAID: 130000069060
  • Peer Reviewed
• [Journal Article] Chronic urotensin II infusion enhances macrophage foam cell formation and atherosclerosis in apolipoprotein E-knockout mice. (2008)
  • Author(s): Shiraishi Y, Watanabe T, Suguro T, Nagashima M, Kato R, Hongo S, Itabe H, Miyazaki A, Hirano T, Adachi M.
  • Journal Title: J. Hypertens. 26 Pages: 1955-1965
  • Peer Reviewed
• [Journal Article] Analyses of group III secreted phospholipase A2 transgenic mice reveals potential participation of this enzyme in plasma lipoprotein modification, macrophage foam cell Formation, and atherosclerosis. (2008)
  • Author(s): Sato H, Kato R. Isogai Y, Saka G, Ohtsuki M, Taketomi Y, Yamamoto K, Tsutsumi K, Yamada J, Masuda S, Ishikawa Y, Ishii T, Kobayashi T, Ikeda K, Taguchi R, Hatakeyama S, Hara S. Kudo I, Itabe H, Murakami M.
  • Journal Title: J. Biol. Chem. 283 Pages: 33483-33497
  • Peer Reviewed
• [Journal Article] Invasion of atherosclerotic plaque into tunica media causes coronary outward remodeling in WHHLMI rabbits. (2008)
  • Author(s): Shiomi M, Yamada S, Matsukawa A, Itabe H, Ito T.
  • Journal Title: Atherosclerosis 198 Pages: 287-293
  • Peer Reviewed
• [Journal Article] Ox-LDL activates PPARα and PPARγ through MAPK-dependent COX-2 expression in macrophages. (2008)
  • Author(s): Taketa K, Matsumura T, Yano M, Ishii N, Senokuchi T, Motoshima H, Murata Y, Kim-Mitsuyama S, Kawada T, Itabe H, Takeya M, Nishikawa T, Tsuruzoe K, Araki E.
  • Journal Title: J. Biol. Chem. 283 Pages: 9852-9862
  • Peer Reviewed
• [Journal Article] A tryrosine kinase inhibitor,β-hydroxyisovalerylshikonin,inducepoptosis in human lung cancer DMS114 cells through reduction of dUTP nucleotidohydrolase activity (2008)
  • Author(s): Kajimoto S, Horie M, Manabe H, Masuda Y, Shibayama-lmazu T, Nakajo S, Xiang Feng Gong, Obama T, Itabe H, Nakaya K.
  • Journal Title: BBA-Molecular Basis of Disease. 1782 Pages: 41-50
  • Peer Reviewed
• [Journal Article] Protection agahlst oxidative stress-hlduced 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: Journal of Biological Chemistry 283 Pages: 1628-1636
  • Peer Reviewed
• [Journal Article] Induction of apoptosis in PA-10varian cancer cells by vitamin K2 isassociated with an increase in the level of TR3/Nur77 and itsaccumulation in mitochondria and nuclei (2008)
  • Author(s): Shibayama-lmazu T, Fupsawa Y, Masuda Y, Aiuchi T, Nakajo S, Itabe H, Nakaya K.
  • Journal Title: J.Can.Res.Clip.Oncol.
  • Peer Reviewed
• [Journal Article] Invasion of atherosclerotic plaque into tunica media causes coronaoutward remodeling in WHHLMI rabbits (2008)
  • Author(s): Shiomi, M., Yamada, S.; Matsukawa, A., Itabe, H., Ito, T.
  • Journal Title: Atherosclerosis
  • Peer Reviewed
• [Journal Article] Analysis of modified apolipoprotein B-100 structures formed in oxidized low-density lipoprotein using LC-MS/MS (2007)
  • Author(s): Obama T, Kato R, Masuda Y, Takahashi K, Aiuchi T, and Itabe H.
  • Journal Title: Proteomics 7 Pages: 2132-2141
• [Journal Article] Involvement of long chain acyl-CoA synthetase in local synthesis of neutral lipids in cytoplasmic lipid droplets in human hepatocyte HuH7 (2007)
  • Author(s): Fujimoto Y, Itabe H, Kinoshita T, Homma KJ, Onoduka J, Mori M, Yamaguchi S, Makita M, Higashi Y, Yamashita A, Takano T.
  • Journal Title: J. Lipid Res. 48 Pages: 1280-1292
• [Journal Article] Scavenger receptors for oxidized lipoprotein in age-related maculadegeneration (2007)
  • Author(s): Kamei M, Yoneda K, Kume N, Suzuki M, Itabe H, Matsuda K, Shimaoka T, Minami M, Yonehara S, Kita T, Kinoshita S.
  • Journal Title: Investigative Ophthalmology and Visual Science 58 Pages: 1801-1807
  • Peer Reviewed
• [Journal Article] Elevated plasma levels of oxidized low-density lipoprotein relate to the presence of angiographically detected complex and thrombotic coronary artery lesion morphology in patients with unstable angina (2007)
  • Author(s): Yamashita H, Ehara S, Yoshiyama M, Naruko T, Haze K, Shirai N, Sugama Y, Ikura Y, Ohsawa M, Itabe H, Kataoka T, Kobayashi Y, Becker AE, Yoshikawa J, Ueda M.
  • Journal Title: Circulation Journal 71 Pages: 681-687
  • NAID: 110006273602
  • Peer Reviewed
• [Journal Article] Oxidized phospholipids in the macula increase with age and in eyes with age-related macular degeneration (2007)
  • Author(s): Suzuki M, Kamei M, Itabe H, Yoneda K, Bando H, Kume N, Tano Y.
  • Journal Title: Molecular Vision 13 Pages: 772-778
  • Peer Reviewed
• [Journal Article] Analysis of modified apolipoprotein B-100 structures formed in oxidized low-density lipoprotein using LC-MS/MS (2007)
  • Author(s): Obama T, Kato R, Masuda Y, Takahashi K, Aiuchi T, Itabe H.
  • Journal Title: Proteomics 7 Pages: 2132-2141
  • Peer Reviewed
• [Journal Article] Distinguished effects of antiphospholipid antibodies and anti-oxidizedLDL antibodies on oxidized LDL uptake by macrophages (2007)
  • Author(s): Kobayashi K, Tada K, Itabe H, Ueno T, Liu PH, Tsutsumi A, Kuwana M, Yasuda T, Shoenfeld Y, de Groot PG, Matsuura E.
  • Journal Title: Lupus 16 Pages: 929-938
  • Peer Reviewed
• [Journal Article] Negative feedback loop in bim-caspase-3 axis regulating apoptosis andctivity of osteoclasts (2007)
  • Author(s): Wakeyama H, Akiyama T, Takahashi K, Amano H, Kadono Y, Nakamura M, Oshima Y, Itabe H, Nakayama KI, Nakayama K, Nakamura K, Tanaka S.
  • Journal Title: Journal of Bone and Mineral Research 22 Pages: 1631-1639
  • Peer Reviewed
• [Journal Article] Involvement of long chain aeyl-CoA synthetase in local synthesis oneutral lipids in cytoplasmic lipid droplets in human hepatocyte HuH7 (2007)
  • Author(s): Fujimoto Y, Itabe H, Kinoshita T, Homma KJ, Onoduka J, Mori M, Yamaguchi S, Makita M, Higashi Y, Yamashita A, Takano T.
  • Journal Title: Journal of Lipid Research. 48 Pages: 1280-1292
  • Peer Reviewed
• [Journal Article] Docosahexaenoic acid induces adipose differentiation-related protein through activation of retinoid X receptor in human choriocarcinoma BeWo cells
  • Author(s): Suzuk K, Takahashi K, Mogami NT, Kagechika H, Yamamoto M, Itabe H.
  • Journal Title: Biol. Pharm. Bull. (印刷中)
  • NAID: 130000117213
  • Peer Reviewed
• [Journal Article] Detection of oxidized low-density lipoproteins in gingival crevicular fluid from dentalpatients
  • Author(s): Sakiyama Y, Kato R. Inoue S, Suzuki K, Itabe H, Yamamoto M.
  • Journal Title: J. Perodont. Res. (印刷中)
  • Peer Reviewed
• [Journal Article] Interleukin-10 correlates with oxidized low density lipoprotein in coronary culprit plaques.
  • Author(s): Nishihira K, Imamura T, Ishikawa T, Yamashita A, Shibata Y, Itabe H, Kitamura K, Asada Y.
  • Journal Title: Thromb. Res. (印刷中)
  • Peer Reviewed
• [Presentation] Structure and generation of plasma oxidized LDL during the atherogenesis. (2008)
  • Author(s): H. Itabe.
  • Organizer: Lipid Peroxidation 2008
  • Place of Presentation: 軽井沢
  • Year and Date: 2008-10-15
• [Presentation] Structure and generation of plasma oxidized LDL during the atherogenesis (2008)
  • Author(s): H. Itabe.
  • Organizer: Lipid Peroxidation 2008
  • Place of Presentation: 軽井沢
• [Presentation] Behavior of plasma oxidized LDL levels during the early stage of atherosclerosis on apoHpoproteiE knockout mice (2007)
  • Author(s): H Itabe
  • Organizer: Oxidative Sress Summit
  • Place of Presentation: リーガロイヤルホテル、大阪
  • Year and Date: 2007-07-15
• [Presentation] Induction of intracellular lipid droplet proteins by lipids in pathological conditions (2007)
  • Author(s): H. Itabe, Y. Masuda, N. Sasabe, K. Kitazato, K. Takahashi, J. Aoki, H. Arai, and T. Takano.
  • Organizer: The 3rd International Conference on Phospholipase A_2 and Lipid Mediators
  • Place of Presentation: Sorrento, Italy
• [Presentation] Behavior of plasma oxidized LDL levels during the early stage of atherogenesis in apolipoprotein E knockout mice (2007)
  • Author(s): H. Itabe.
  • Organizer: Oxidative Stress Summit
  • Place of Presentation: 大阪
• [Presentation] Atherosclerosis and inflammation: a perspective through oxidized low-density lipoprotein (2007)
  • Author(s): H. Itabe.
  • Organizer: The 1st International Symposium on Development of Anti-inflammatory Drugs
  • Place of Presentation: Gyeongsan, Korea
• [Presentation] Induction of intracellular lipid droplet proteins by lipids in pathological conditions (2007)
  • Author(s): H Itabe
  • Organizer: International Conference on Phospholipase A2 and Lipid Mediators
  • Place of Presentation: Dorrento,Italy
• [Presentation] 酸化LDL研究の最前線〜overview (2007)
  • Author(s): 板部 洋之
  • Organizer: 第39回日本動脈硬化学会
  • Place of Presentation: 大阪国際会議場、大阪
• [Book] 酸化ストレスの医学 (2008)
  • Author(s): 小浜孝士, 板部洋之, 他80名
  • Total Pages: 384
  • Publisher: 診断と治療社
• [Book] "New Frontiers in Lifestyle-related Disease."eds.By Miyazaki, A.and Imawari, M. (2007)
  • Author(s): Itabe, H., Masuda, Y., Sasabe, N. Kitazato, K., Arai, H., Takano, T.
  • Total Pages: 160
  • Publisher: Springer(Tokyo)