Studies on process of generation and metabolism of oxidized LDL in vivo.

• Project/Area Number: 15K07944
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Showa University
• Principal Investigator: ITABE Hiroyuki 昭和大学, 薬学部, 教授 (30203079)
• Co-Investigator(Kenkyū-buntansha): 山口 智広 昭和大学, 薬学部, 准教授 (50347530) ; 小濱 孝士 昭和大学, 薬学部, 准教授 (60395647) ; 加藤 里奈 昭和大学, 薬学部, 助教 (30392400) ; 笹部 直子 昭和大学, 薬学部, 助教 (50643566)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 酸化LDL / 動脈硬化 / 質量分析 / 安定同位体標識 / リピドミクス / リポタンパク質 / LC-MS/MS / 酸化リン脂質 / LCAT / リゾPC / Lp-PLA2 / リゾホスファチジルコリン

Outline of Final Research Achievements

Metabolic fate of oxidized phosphatidylcholine (oxPC) produced in oxidixed low-density lipoprotein (oxLDL) was investigated using deuterium-labeled lysoPC and oxPC. A labeled oxPC (d13-PGPC) was converted rapidly in LDL, but lysoPC was not generated in the presence of an Lp-PLA2 inhibitor. When LDL containing d13-lysoPC was incubated with HDL at 37C, d13-lysoPC decreased in a time-dependent manner to less than 50% in 4 h. In the same time, a variety of diacyl-PC derived from the d13-lysoPC were produced. d13-lysoPC was able to transfer between LDL and HDL particles, and the generated diacyl-PCs distributed to both LDL and HDL. Reacylation of lysoPC did not occur in the absence of HDL and was blocked by addition of DTNB, an LCAT inhibitor. From these results, it was demonstrated that oxPC in LDL can be metabolized by multiple enzymes and reacylated to form diacyl-PC under the conditions that HDL can interact with LDL.

Research Products

• [Journal Article] Significance of oxidized low-density lipoprotein in body fluids as a marker related to diseased conditions. (2018)
  • Author(s): Itabe Hiroyuki、Kato Rina、Sasabe Naoko、Obama Takashi、Yamamoto Matsuo
  • Journal Title: Curr Med Chem Volume: 25 Issue: 9 Pages: 1576-1593
  • DOI: 10.2174/0929867325666180307114855
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantitative proteomic analysis of gingival crevicular fluids from deciduous and permanent teeth. (2017)
  • Author(s): Moriya Y, Obama T, Aiuchi T, Sugiyama T, Endo Y, Koide Y, Noguchi E, Ishizuka M, Inoue M, Itabe H, Yamamoto M.
  • Journal Title: Journal of Clinical Periodontology Volume: 印刷中 Issue: 4 Pages: 353-362
  • DOI: 10.1111/jcpe.12696
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Perilipins: A diversity of intracellular lipid droplet proteins. (2017)
  • Author(s): Hiroyuki Itabe, Tomohiro Yamaguchi, Satomi Nimura, Naoko Sasabe
  • Journal Title: Lipids in Health and Diseases Volume: 16 Issue: 1 Pages: 83-83
  • DOI: 10.1186/s12944-017-0473-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Morphological features of coronary plaques in WHHLMI rabbits (<i>Oryctolagus cuniculus</i>), an animal model for familial hypercholesterolemia (2017)
  • Author(s): Yamada S, Koike T, Nakagawa T, Kuniyoshi, N Ying Y, Itabe H, Yamashita A, Asada Y, Shiomi M.
  • Journal Title: Experimental Animals Volume: 66 Issue: 2 Pages: 145-157
  • DOI: 10.1538/expanim.16-0078
  • NAID: 130005635564
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Changes in apolipoprotein B and oxidized low-density lipoprotein levels in gingival crevicular fluids caused by periodontal tissue conditions. (2017)
  • Author(s): Ishizuka M, Kato R, Moriya Y, Noguchi E, Koide Y, Inoue S, Itabe H, Yamamoto M.
  • Journal Title: Journal of Periodontal Research Volume: 印刷中 Issue: 3 Pages: 594-602
  • DOI: 10.1111/jre.12427
  • Peer Reviewed / Open Access
• [Journal Article] Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing. (2016)
  • Author(s): Miyazaki T, Tonami K, Hata S, Aiuchi T, Ohnishi K, Lei XF, Kim-Kaneyama JR, Takeya M, Itabe H, Sorimachi H, Kurihara H, Miyazaki A
  • Journal Title: J Clin Invest Volume: 126 Issue: 9 Pages: 3417-3432
  • DOI: 10.1172/jci85880
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nephronectin Expression Is Up-Regulated by BMP-2 (2016)
  • Author(s): Kurosawa T, Yamada A, Suzuki D, Morimura N, Sasagane Y, Itabe H, Kamijo R
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 39 Issue: 7 Pages: 1211-1215
  • DOI: 10.1248/bpb.b15-00941
  • NAID: 130005160772
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of HIC-5 in the formation of microvilli-like structures and the monocyte-endotherial interaction that accelerates atherosclerosis (2015)
  • Author(s): Shigeko Arita-Okubo, et al
  • Journal Title: Cardiovasc Res Volume: 105 Issue: 3 Pages: 361-371
  • DOI: 10.1093/cvr/cvv003
  • Peer Reviewed / Open Access
• [Journal Article] Dietary Cholesterol Atherogenic Changes in Juvenile Rabbits (2015)
  • Author(s): Keyamura Y, Nagano C, Kohashi M, Niimi M, Nozako M, Koyama T, Itabe H, Yoshikawa T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 38 Issue: 5 Pages: 785-788
  • DOI: 10.1248/bpb.b14-00775
  • NAID: 130005068094
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Tomohiro Yamaguchi, Noriyuki Fujikawa, Satomi Nimura, Yutaro Tokuoka, Sonoka Tsuda, Toshihiro Aiuchi, Rina Kato, Takashi Obama, Hiroyuki Itabe. Characterization of lipid droplets in steroidogenic MLTC-1 Leydig cells: Protein profiles and the morphological change induced by hormone stimulation. (2015)
  • Author(s): Yamaguchi T, Fujikawa N, Nimura S, Tokuoka Y, Tsuda S, Aiuchi T, Kato R, Obama T, Itabe H.
  • Journal Title: BBA - Molecular and Cell Biology of Lipids Volume: 1851 Issue: 10 Pages: 1285-1295
  • DOI: 10.1016/j.bbalip.2015.06.007
  • Peer Reviewed
• [Journal Article] Olanzapine promotes the accumulation of lipid droplets and the expression of multiple perilipins in human adipocytes. (2015)
  • Author(s): Nimura S, Yamaguchi T, Ueda K, Kadokura K, Aiuchi T, Kato R, Obama T, Itabe H.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 467 Issue: 4 Pages: 906-912
  • DOI: 10.1016/j.bbrc.2015.10.045
  • Peer Reviewed
• [Presentation] 血管内皮細胞の炎症誘導における好中球細胞外トラップと酸化LDLの関与」 日本薬学会第138年会 (2018)
  • Author(s): 小浜孝士、池田葵、今井瑞菜、上田晃輝、門倉夏林、髙橋江里奈、澤田直子、相内敏弘、加藤里奈、板部洋之
  • Organizer: 日本薬学会第138年会
• [Presentation] 動脈硬化初期病変進展過程における抗酸化タンパク質Peroxiredoxin 2及びThioredoxin低下による平滑筋細胞の酸化ストレス亢進 (2018)
  • Author(s): 加藤里奈、嶋崎萌夏、小澤雪乃、知念良憲、渡辺窓香、上當明徳、高田紫苑、相内敏弘、澤田直子、小浜孝士、板部洋之
  • Organizer: 日本薬学会第138年会
• [Presentation] 動脈硬化症患者血漿中の酸化LDLの分離とその性状解析 (2018)
  • Author(s): 澤田直子、小浜 孝士、巖本三壽、木庭新治、相内敏弘、加藤里奈、板部洋之
  • Organizer: 日本薬学会第138年会
• [Presentation] 安定同位体リピドミクスを用いたHDLによるLDL酸化抑制機構の解析 (2017)
  • Author(s): 笹部直子、小浜孝士、増田しおり、髙田夏鈴、相内敏弘、加藤里奈、板部洋之
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-24
• [Presentation] 動脈硬化初期病変進展過程における平滑筋細胞の酸化ストレス上昇と形質変化の関係性 (2017)
  • Author(s): 加藤里奈、嶋﨑萌夏、鈴木花菜、小澤雪乃、知念良憲、渡辺窓香、相内敏弘、笹部直子、小浜孝士、板部洋之
  • Organizer: 第49回日本動脈硬化学会・学術集会
• [Presentation] 歯肉溝滲出液中の酸化LDLと歯周病に伴う炎症について (2017)
  • Author(s): 石塚元規、板部洋之、加藤里奈、守屋佑美、山本松男、笹部直子、小浜孝士
  • Organizer: 第59回日本脂質生化学会
• [Presentation] 生体内酸化LDLの実態について：生成・代謝・輸送と疾患 (2017)
  • Author(s): 板部洋之
  • Organizer: 日本過酸化脂質・抗酸化物質学会第25回会年回
  • Invited
• [Presentation] 動脈硬化進展初期過程における平滑筋細胞のPerxoiredoxin 2低下による酸化ストレス亢進と形質変化 (2017)
  • Author(s): 加藤里奈、嶋﨑萌夏、鈴木花菜、小澤雪乃、知念良憲、渡辺窓香、相内敏弘、笹部直子、小浜孝士、板部洋之
  • Organizer: ConBio2017
• [Presentation] HDLによるLDL中の酸化PC代謝の安定同位体リピドミクスを用いた解析 (2017)
  • Author(s): 笹部直子、小浜孝士、増田しおり、高田夏鈴、櫻井彩伽、長谷川拓也、福原潔、水野美麗、相内敏弘、加藤里奈、板部洋之
  • Organizer: ConBio2017
• [Presentation] ヒト血漿から分離した酸化LDLに含まれる酸化リン脂質と変性タンパク質の解析 (2016)
  • Author(s): 笹部 直子、小浜 孝士、井上 望、橋本 哲弥、久保 祐貴、巖本 三壽、相内 敏弘、加藤 里奈、板部 洋之
  • Organizer: 衛生薬学・環境トキシロジーフォーラム2016
  • Place of Presentation: 東京
  • Year and Date: 2016-09-10
• [Presentation] ヒト血漿からの酸化LDL分離と脂質酸化による性状の変化 (2016)
  • Author(s): 小浜孝士、笹部直子、井上望、橋本哲弥、久保祐貴、巖本 三壽、相内敏弘、加藤里奈、板部洋之
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: 秋田
  • Year and Date: 2016-06-09
• [Presentation] 安定同位体リピドミクスによる酸化LDL-HDL間の脂質利モデリングの解析 (2016)
  • Author(s): 増田しおり、高田夏鈴、小浜孝士、相内敏弘、加藤里奈、山口智広、板部洋之
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
• [Presentation] Reduced expression of peroxiredoxin 2 in smooth muscle cells at the onset of atherogenesis in apoE-knockout mice. (2015)
  • Author(s): Itabe H, Kato R, Hayashi M, Obama T, Aiuchi T, Yamaguchi T.
  • Organizer: 11th International Congress on Coronary Artery Disease
  • Place of Presentation: フローレンス
  • Year and Date: 2015-11-29
  • Int'l Joint Research
• [Remarks] 生物化学部門のホームページ
  • URL: http://www10.showa-u.ac.jp/~biolchem/