Evaluation of new nanotechnology to raise HDL cholesterol level and elucidation of its molecular mechanism

• Project/Area Number: 23659463
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: University of Tsukuba
• Principal Investigator: SHIMANO Hitoshi 筑波大学, 医学医療系, 教授 (20251241)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Akimitsu 筑波大学, 医学医療系, 准教授 (70344893) ; MATSUZAKA Takashi 筑波大学, 医学医療系, 准教授 (70400679)
• Project Period (FY): 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2011: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: リポタンパク質 / 動脈硬化 / 胆汁酸 / ナノテクノロジー / 脂質異常症

Research Abstract

Raising HDL-cholesterol (C) has emerged as a potential strategy to tackle the residual risk that remains even after lowering LDL-C and triglyceride, in preventing cardiovascular disease. PEGylated and quaternized polyamine nanogel (Q-Nanogel) is a newly synthesized bile salt sequestering agent intended to treat dyslipidemia. We assessed the effects of Nanogel on dyslipidemia and atherosclerosis. Nanogel treatment resulted in a 35% reduction in plasma VLDL/LDL-C levels, a 58% increase in plasma HDL-C levels in C57BL/6J mice. In LDLR-/-mice, atherosclerotic lesion size with Nanogel was reduced by 45% compared to PBS. These data indicate that Nanogel not only decreased VLDL/LDL-C levels but also raised HDL-C levels. Nanogel could be a potential therapeutic candidate to raise HDL-C and the treatment of atherosclerosis.

Research Products

• [Journal Article] TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice (2012)
  • Author(s): Iwasaki H, Naka A, Iida KT, Nakagawa Y, Matsuzaka T, Ishii KA, Kobayashi K, Takahashi A, Yatoh S, Yahagi N, Sone H, Suzuki H, Yamada N, Shimano H.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 302(7) Pages: 896-902
  • Peer Reviewed
• [Journal Article] Novel qualitative aspects of tissue fatty acids related to metabolic regulation : Lessons from Elovl6 knockout (2012)
  • Author(s): Shimano H
  • Journal Title: Prog Lipid Res Volume: (in press)
  • Peer Reviewed
• [Journal Article] TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice (2012)
  • Author(s): Iwasaki H, Naka A, Matsuzaka T, Shimano H, et al
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 302(7)
  • Peer Reviewed
• [Journal Article] Novel qualitative aspects of tissue fatty acids related to metabolic regulation : Lessons from Elvol6 knockout (2012)
  • Author(s): Shimano H
  • Journal Title: Prog Lipid Res Volume: (in press)
  • Peer Reviewed
• [Journal Article] Suppression of the pancreatic duodenal homeodomain transcription factor-1 (Pdx-1) promoter by sterol regulatory element-binding protein-1c (SREBP-1c) (2012)
  • Author(s): Amemiya-Kudo M, Yamada N, Murase T, Shimano H, et al
  • Journal Title: J Biol Chem Volume: 286(32) Pages: 27902-14
  • Peer Reviewed
• [Journal Article] Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice (2011)
  • Author(s): Saito R, Matsuzaka T, Karasawa T, Sekiya M, Okada N, Igarashi M, Matsumori R, Ishii K,Nakagawa Y, Iwasaki H, Kobayashi K, YatohS, Takahashi A, Sone H, Suzuki H, Yahagi N,Yamada N, Shimano H
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(9) Pages: 1973-9
  • Peer Reviewed
• [Journal Article] Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7α (Fbw7α) causes hepatosteatosis through Kruppel-like factor 5(KLF5)/peroxisome proliferator-activatedreceptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice (2011)
  • Author(s): Kumadaki S, Karasawa T, Matsuzaka T, EmaM, Nakagawa Y, Nakakuki M, Saito R,Yahagi N, Iwasaki H, Sone H, Takekoshi K,Yatoh S, Kobayashi K, Takahashi A, SuzukiH, Takahashi S, Yamada N, Shimano H
  • Journal Title: J Biol Chem Volume: 286(47) Pages: 40835-46
  • Peer Reviewed
• [Journal Article] Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice. (2011)
  • Author(s): Karasawa T, Takahashi A, Saito R, Sekiya M,Igarashi M, Iwasaki H, Miyahara S,Koyasu S, Nakagawa Y, Ishii K, Matsuzaka T, Kobayashi K, Yahagi N, Takekoshi K, Sone H, Yatoh S, Suzuki H, Yamada N,S himano H
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(8) Pages: 1788-95
  • Peer Reviewed
• [Journal Article] Suppression of the pancreatic duodenal homeodomain transcription factor-1 (Pdx-1) promoter by sterol regulatory element-binding protein-1c (SREBP-1c) (2011)
  • Author(s): Amemiya-Kudo M, Oka J, Takeuchi Y, Okazaki H, Yamamoto T, Yahagi N, Matsuzaka K, Okazaki S, Osuga J, Yamada N, Murase T, Shimano H
  • Journal Title: J Biol Chem Volume: 286(32) Pages: 27902-14
  • Peer Reviewed
• [Journal Article] Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7α (Fbw7α) causes hepatosteatosis through Kruppel-like factor 5 (KLF5)/peroxisome proliferator-activated receptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice (2011)
  • Author(s): Kumadaki S, Matsuzaka T, Yamada N, Shimano H, et al
  • Journal Title: J Biol Chem Volume: 286(47) Pages: 40835-46
  • Peer Reviewed
• [Journal Article] Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density liporotein receptor-deficient mice (2011)
  • Author(s): Saito R, Matsuzaka T, Yamada N, Shimano H, et al
  • Journal Title: Arterioscle Thromb Vasc Biol Volume: 31(9) Pages: 1973-9
  • Peer Reviewed
• [Journal Article] HbA1c 5.7-6.4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3) : a longitudinal cohort study (2011)
  • Author(s): Heianza Y, Shimano H, Yamada N, Sone H, et al
  • Journal Title: Lancet Volume: 378(9786) Pages: 147-55
  • Peer Reviewed
• [Journal Article] Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice (2011)
  • Author(s): Karasawa T, Matsuzaka T, Yamada N, Shimano H, et al
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(8) Pages: 1788-95
  • Peer Reviewed
• [Presentation] "PEGylated and quaternized polyamine nanogel", a brand-new bile acid sequestrant, ameliorates lipoprotein profiles and reduces atherosclerosis in low-density-lipoprotein receptor deficient and apolipoprotein E deficient mice (2012)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第76回日本循環器病学会
  • Place of Presentation: 福岡国際会議場(福岡市)
  • Year and Date: 2012-03-17
• [Presentation] A novel bile salt sequestering agent_PEGylated and quaternized polyamine nanogel reduces VLDL and LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第84回米国心臓協会学術集会(AHA Scientific Sessions2011)
  • Place of Presentation: Orange Country Convention Center, Orlando, Florida,USA
  • Year and Date: 2011-11-15
• [Presentation] A novel bile salt sequestering agent "PEGylated and quaternized polyamine nanogel" reduces YLDL and LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第84回米国心臓協会学術集会(AHA Scientific Sessions 2011)
  • Place of Presentation: アメリカ(フロリダ)
  • Year and Date: 2011-11-15
• [Presentation] PEGylated and quaternized polyaminena nogel a novel bile salt sequestering agent, ameliorates dyslipidmia through reduction of VLDL and LDL cholesterol, and induction of HDL cholesterol (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第43回日本動脈硬化学会学術集会
  • Place of Presentation: ロイトン札幌、札幌
  • Year and Date: 2011-07-16
• [Presentation] "PEGylated and quaternized polyamine nanogel" a novel bile salt sequestering agent, ameliorates dyslipidmia through reduction of VLDL and LDL cholesterol, and induction of HDL cholesterol (2011)
  • Author(s): Rie Matsumori, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第43回日本動脈硬化学会学術集会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2011-07-16
• [Presentation] 動脈硬化戦略における脂質管理の新しい視点:臓器脂質の量的制御と質的制御 (2011)
  • Author(s): 島野仁
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌、札幌
  • Year and Date: 2011-05-20
• [Presentation] 動脈硬化戦略における脂質管理の新しい視点:臓器脂質の量的制御と質的制御 (2011)
  • Author(s): 島野仁
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌(札幌市)(招待講演)
  • Year and Date: 2011-05-20
• [Presentation] 飢餓応答肝臓特異的転写因子CREBHの糖脂質代謝制御 (2011)
  • Author(s): 島野仁
  • Organizer: 第84回日本内分泌学会年次学術集会
  • Place of Presentation: 神戸国際会議場(神戸市)(招待講演)
  • Year and Date: 2011-04-21
• [Presentation] Anovel bile salt sequestering agent PEGylated and quaternized polyamine nanogel reduces VLDL and LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Haruna Shinozaki, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、横浜
• [Presentation] A novel bile salt sequestering agent PEGylated and quaternized polyamine nanogel reduces VLDL and LDL cholesterol, raises HDL cholesterol, and prevents atherosclerosis in mice (2011)
  • Author(s): Haruna Shinozaki, Takashi Matsuzaka, Yukio Nagasaki, Hitoshi Shimano, et al
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
• [Remarks]
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Remarks]
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Patent(Industrial Property Rights)] 高分子化環状ニトロキシドラジカル化合物の経口投与用製剤 (2012)
  • Inventor(s): 長崎幸夫、吉冨徹、尾崎裕樹、ペナパーショパトンピクンラット、島野二、松坂賢、唐澤直義
  • Industrial Property Rights Holder: 筑波大学
  • Industrial Property Number: 2012-019975
  • Filing Date: 2012-01-13