Development of a novel therapy for atherosclerosis based on alleviation of lipotoxicity of macrophages

• Project/Area Number: 25293213
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Jichi Medical University
• Principal Investigator: ISHIBASHI SHUN 自治医科大学, 医学部, 教授 (90212919)
• Co-Investigator(Kenkyū-buntansha): NAGASHIMA SHUICHI 自治医科大学, 医学部, 講師 (30406136) ; TAKAHASHI MANABU 自治医科大学, 医学部, 講師 (70406122) ; YAMAMURO DAISUKE 自治医科大学, 医学部, リサーチレジデント (20739255) ; 坂井 謙斗 自治医科大学, 医学部, ポストドクター (30646352) ; 大須賀 淳一 自治医科大学, 医学部, 准教授 (10334400)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 動脈硬化 / 泡沫細胞 / マクロファージ / コレステロール / リパーゼ / トランスジェニック / マウス / 小胞体ストレス / オキシステロール / 酵素 / 加水分解 / 脂肪酸 / 小胞体 / アポトーシス / エステル

Outline of Final Research Achievements

Foam cells in atheromatous lesions are characterized by macrophages loaded with cholesteryl ester in lipid droplets. The cellular CE is hydrolyzed not only by hormone-sensitive lipase (Lipe) but also by neutral CE hydrolase 1 (NCEH1), which we identified as a unique CE hydrolase functional in human and murine macrophages. It is plausible that overexpression of NCEH1 in macrophages is protective against atherosclerosis not only by reducing the burden of CE, but also alleviating other immunological lipotoxicity. To test these hypotheses, we have generated mice overexpoessing Nceh1 or Lipe in a macrophage-specific manner using Cre/lox technology. The peritoneal macrophages expressed 3-fold higher levels of mRNA compared with those from wild-type mice. We are going to examine the effects of the transgene on the development of atherosclerosis.

Research Products

• [Journal Article] Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver. (2015)
  • Author(s): Nagashima S, Yagyu H, Tozawa R, Tazoe F, Takahashi M, Kitamine T, Yamamuro D, Sakai K, Sekiya M, Okazaki H, Osuga J, Honda A, Ishibashi S.
  • Journal Title: J Lipid Res Volume: 56 Issue: 5 Pages: 998-1005
  • DOI: 10.1194/jlr.m057406
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] New pyripyropene derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse model. (2015)
  • Author(s): Ohshiro, T.; Ohtawa, M.; Nagamitsu, T.; Matsuda, D.; Yagyu, H.; Davis, M. A.; Rudel, L. L.; Ishibashi, S.; Tomoda, H.
  • Journal Title: Journal of Pharmacology and Experimental Therapeutics Volume: 355 Issue: 2 Pages: 299-309
  • DOI: 10.1124/jpet.115.227348
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy. (2015)
  • Author(s): Osaki Y, Nakagawa Y, Miyahara S, Iwasaki H, Ishii A, Matsuzaka T, Kobayashi K, Yatoh S, Takahashi A, Yahagi N, Suzuki H, Sone H, Ohashi K, Ishibashi S, Yamada N, Shimano H
  • Journal Title: Biochem Biophys Res Commun. Volume: 466(3) Issue: 3 Pages: 536-540
  • DOI: 10.1016/j.bbrc.2015.09.065
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical role of neutral cholesteryl ester hydrolase 1 in cholesteryl ester hydrolysis in murine macrophages (2014)
  • Author(s): Sakai K, Igarashi M, Yamamuro D, Ohshiro T, Nagashima S, Takahashi M, Enkhtuvshin B, Sekiya M, Okazaki H, Osuga J, Ishibashi S.
  • Journal Title: J Lipid Res Volume: 55 Issue: 10 Pages: 2033-2040
  • DOI: 10.1194/jlr.m047787
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages. (2014)
  • Author(s): Sekiya M, Yamamuro D, Ohshiro T, Honda A, Takahashi M, Kumagai M, Sakai K, Nagashima S, Tomoda H, Igarashi M, Okazaki H, Yagyu H, Osuga J, Ishibashi S.
  • Journal Title: J Lipid Res Volume: 55 Issue: 10 Pages: 2082-2092
  • DOI: 10.1194/jlr.m050864
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Macrophage lipoprotein lipase modulates the development of atherosclerosis but not adiposity (2013)
  • Author(s): Takahashi M, Yagyu H, Tazoe F, Nagashima S, Ohshiro T, Okada K, Osuga J, Goldberg IJ, Ishibashi S.
  • Journal Title: J Lipid Res Volume: 54(4) Issue: 4 Pages: 1124-34
  • DOI: 10.1194/jlr.m035568
  • Peer Reviewed
• [Presentation] 動脈硬化とマクロファージ：コレステロールエステル水解機構を中心に (2015)
  • Author(s): 石橋俊
  • Organizer: 日本動脈硬化学会年次学術集会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2015-07-09
  • Invited
• [Presentation] コレステロールエステル水解反応によるマクロファージ制御 (2015)
  • Author(s): 石橋俊
  • Organizer: 日本糖尿病学会年次学術集会
  • Place of Presentation: 下関市民会館
  • Year and Date: 2015-05-23
  • Invited