Function of apoE in lipoprotein metabolism and atherosclerosis: insight from apoE-deficient rabbit model

• Project/Area Number: 17K08783
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: University of Yamanashi
• Principal Investigator: NIIMI Manabu 山梨大学, 大学院総合研究部, 助教 (80644898)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 脂質異常症 / リポタンパク代謝 / アポE / ウサギ / 遺伝子欠損 / アポリポ蛋白E / リポ蛋白代謝 / 動脈硬化 / ノックアウト / ゲノム編集 / 脂質代謝 / トランスレーショナルリサーチ / 実験病理学

Outline of Final Research Achievements

Apolipoprotein E (apoE) is a 34 kDa glycoprotein and its role on lipid metabolism is a ligand for lipoprotein receptor on the liver. We created apoE-deficient model using rabbits, which have more similar lipoprotein metabolism to humans than mice. To investigate the role of apoE in lipoprotein metabolism and atherosclerosis, we analyzed plasma lipids, lipoproteins and susceptibility to a diet-induced atherosclerosis of apoE-deficient rabbits. ApoE-deficent rabbits showed higher plasma total cholesterol and triglycerides levels than those of wild-type rabbits on a high cholesterol-diet. This increase was due to an elevated plasma βVLDL, and the βVLDL showed enriched apoB-48. Our studies revealed that deficiency of apoE in rabbits promotes aortic atherosclerosis.

Academic Significance and Societal Importance of the Research Achievements

脂質異常症は動脈硬化を引き起こす原因の一つで、心筋梗塞などの心血管疾患における重要な危険因子である。脂質異常症は遺伝素因、生活習慣などさまざまな原因で発症する。アポリポ蛋白E（アポE）もその原因の一つで、アポEに変異や欠損が生じると血中リポ蛋白の肝臓での受容体結合能が低下し、Ⅲ型高脂血症を引き起こす。これまでにアポE欠損マウスを用いた研究が盛んに行われてきた。本研究ではマウスに比べてヒトにより近いリポ蛋白代謝系を持つウサギを用いてアポEのリポ蛋白代謝及び動脈硬化形成・進展における役割を明らかにした。

Research Products

• [Int'l Joint Research] ミシガン大学メディカルセンター(米国)
• [Int'l Joint Research] ミシガン大学メディカルセンター(米国)
• [Journal Article] Endothelial Lipase Exerts its Anti-Atherogenic Effect through Increased Catabolism of β-VLDLs (2021)
  • Author(s): Yan H, Niimi M, Wang C, Chen Y, Zhou H, Matsuhida F, Nishijima K, Kitajima S, Nakajima K, Murakami M, Zhang J, Chen YE, Fan J
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 2 Pages: 157-168
  • DOI: 10.5551/jat.55244
  • NAID: 130007979538
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-02-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sex hormones affect endothelial lipase-mediated lipid metabolism and atherosclerosis (2019)
  • Author(s): Wang Chuan、Niimi Manabu、Kitajima Shuji、Matsuhisa Fumikazu、Yan Haizhao、Dong Sijun、Liang Jingyan、Fan Jianglin
  • Journal Title: Lipids in Health and Disease Volume: 18 Issue: 1 Pages: 226-226
  • DOI: 10.1186/s12944-019-1175-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophage-derived matrix metalloproteinase-1 enhances aortic aneurysm formation in transgenic rabbits. (2019)
  • Author(s): Niimi M, Nishijima K, Kitajima S, Matsuhisa F, Satoh K, Yamazaki H, Zhang J, Chen YE, Fan J.
  • Journal Title: J Biomed Res. Volume: in press Issue: 4 Pages: 271-271
  • DOI: 10.7555/jbr.33.20180097
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Detection of potential new biomarkers of atherosclerosis by probe electrospray ionization mass spectrometry (2018)
  • Author(s): Johno Hisashi、Yoshimura Kentaro、Mori Yuki、Kimura Tokuhide、Niimi Manabu、Yamada Masaki、Tanigawa Tetsuo、Fan Jianglin、Takeda Sen
  • Journal Title: Metabolomics Volume: 14 Issue: 4 Pages: 1-6
  • DOI: 10.1007/s11306-018-1334-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Principles and Applications of Rabbit Models for Atherosclerosis Research (2018)
  • Author(s): Fan J, Chen Y, Yan H, Niimi M, Wang Y, Liang J.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 25 Issue: 3 Pages: 213-220
  • DOI: 10.5551/jat.RV17018
  • NAID: 130006407212
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deficiency of Cholesteryl Ester Transfer Protein Protects Against Atherosclerosis in Rabbits. (2017)
  • Author(s): Zhang, J. Niimi, M. Yang, D. Liang, J. Xu, J. Kimura, T. Mattew, A. V. Guo, Y. Fan, Y. Zhu, T. Song, J. Ackermann, R. Koike, Y. Schwendeman, A. Lai, L. Pennathur, S. Garcia-Barrio, M. Fan, J. Chen, Y. E.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: in press Issue: 6 Pages: 1068-1075
  • DOI: 10.1161/atvbaha.117.309114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Increased hepatic expression of endothelial lipase inhibits cholesterol diet induced hypercholesterolemia and atherosclerosis in transgenic rabbits (2017)
  • Author(s): Wang, C., Nishijima, K., Kitajima, S., Niimi, M., Yan, H., Chen, Y., Ning, B., Matsuhisa, F., Liu, E., Zhang, J., Chen, Y. E., Fan. J.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. Volume: 37 Issue: 7 Pages: 1282-1289
  • DOI: 10.1161/atvbaha.117.309139
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative studies of three cholesteryl ester transfer proteins and their interactions with known inhibitors. (2017)
  • Author(s): Wang Z, Niimi M, Ding Q, Liu Z, Wang L, Zhang J, Xu J, Fan J.
  • Journal Title: PLoS One. Volume: 12 Issue: 8 Pages: e0180772-e0180772
  • DOI: 10.1371/journal.pone.0180772
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Endothelial lipase attenuates cholesterol diet-induced hypercholesterolemia and protects against atherosclerosis in transgenic rabbits (2019)
  • Author(s): Niimi M, Wang C, Yan H, Chen Y, Zhou H, Matsuhisa F, Nishijima K, Kitajima S, Zhang J, Chen YE, Fan J
  • Organizer: 42nd Annual Scientific Meeting of the European Lipoprotein Club (ELC)
  • Int'l Joint Research
• [Presentation] Deletion of the apoCIII gene in knockout rabbits enhances the catabolism of triglyceride-rich lipoproteins and attenuates cholesterol diet-induced hyperlipidemia (2019)
  • Author(s): Yan H, Niimi M, Kitajima S, Zhou H, Matsuhisa F, Chen Y, Zhang J, Chen YE, Fan J
  • Organizer: 8th International Congress on Lipid & Atherosclerosis (ICoLA 2019)
  • Int'l Joint Research
• [Presentation] 内皮リパーゼは血中脂質降下を介して抗動脈硬化作用を発揮する (2019)
  • Author(s): 新見 学、Yan Haizhao、Chen Yajie、Zhou Huanjin、王 川、松久 葉一、西島 和俊、北嶋 修司、範 江林
  • Organizer: 第51回日本動脈硬化学会総会・学術集会
• [Presentation] China-Japan International Conference on Atherosclerosis 2018 (2018)
  • Author(s): Niimi M, Fan J.
  • Organizer: CETP inhibition and atherosclerosis therapy: myth or fact.
  • Int'l Joint Research / Invited
• [Presentation] Characterization of apolipoprotein C-III knockout rabbits. (2018)
  • Author(s): Yan H, Niimi M, Matsuhisa F, Kitajima S, Chen YE, Fan J.
  • Organizer: 第5回日本ウサギバイオサイエンス研究会学術集会
• [Presentation] Macrophage-derived matrix metalloproteinase-1 accelerates aortic aneurysm formation in transgenic rabbits. (2017)
  • Author(s): Niimi M, Nishijima K, Kitajima S, Matsuhisa F, Satoh K, Yamazaki H, Fan J.
  • Organizer: 第49回日本動脈硬化学会総会・学術集会
• [Presentation] Increased hepatic expression of endothelial lipase inhibits cholesterol diet-induced hypercholesterolemia and atherosclerosis in transgenic rabbits. (2017)
  • Author(s): Wang C, Nishijima K, Kitajima S, Niimi M, Yan H, Chen Y, Ning B, Matsuhisa F, Liu E, Zhang J, Chen YE, Fan J.
  • Organizer: 7th International Congress on Rabbit Biotechnology 2017
  • Int'l Joint Research
• [Remarks] 山梨大学大学院 総合研究部 医学域 分子病理学講座ホームページ
  • URL: https://www.med.yamanashi.ac.jp/clinical_basic/pathol01/
• [Remarks] 山梨大学大学院 総合研究部 医学域 基礎医学系 分子病理学講座
  • URL: https://www.med.yamanashi.ac.jp/clinical_basic/pathol01/index.html
• [Remarks] 山梨大学大学院総合研究部医学域分子病理学講座
  • URL: https://www.med.yamanashi.ac.jp/clinical_basic/pathol01/