ノンコーディングＲＮＡによる脂質代謝調節を担う転写因子間のクロストーク

• Project Area: Crosstalk of transcriptional control and energy pathways by hub metabolites
• Project/Area Number: 24116512
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 尾野 亘 京都大学, 医学(系)研究科(研究院), 講師 (00359275)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000); Fiscal Year 2013: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2012: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: マイクロRNA / コレステロール / 脂肪酸 / 肥満 / 脂肪肝 / 転写因子 / 脂質代謝

Research Abstract

①miR-33bのSrebf1へのノックインマウスの作成とその解析
miR-33bノックインマウスおよびコントロールマウスにおいてLXRアゴニストを投与したところ、Srebf1およびmiR-33bは平行して発現上昇した。さらにヘテロおよびホモノックインマウスの両者において約35%のHDL-Cの低下を認めた。これらの結果はmiR-33ノックアウトマウスと鏡像関係にあり、生体内でのmiR-33aおよびmiR-33bが同じ標的遺伝子に作用していると考えられた。miR-33aおよびmiR-33bの有無による4種類のマウスの表現系についても検討中である。
②miR-33欠損マウスを用いた解析：miR-33欠損マウスは正常食下でも加齢に伴い肥満と脂肪肝を呈する。高脂質食負荷では若年から肥満、脂肪肝となる。そこで12週令の体重差の無い状況で肝臓のマイクロアレイ解析を行ったところ、脂肪酸合成系遺伝子が最も変化していた。miR-33の標的遺伝子にはSrebf1があり、このヘテロマウスと交配したところ、miR-33欠損で認められた肥満と脂肪肝が消失した。このことから、Srebf2はイントロンのmiR-33aでSrebf1を制御していることになり、新たなSrebf1とSrebf2の間のクロストークがあることが明らかとなった。
③細胞内コレステロール量により制御されるnon-codingRNAの検討：候補のlincRNAを複数見出し、機能解析中である。
④ヒトでのmiR-33a/bの発現レベルと病態との関係についての検討：ヒト肝臓生検サンプルにおいて、発現と組織との関係を検討した。どちらもmiR-33a/bその相補鎖であるmiR-33a*/b*は発現していたが、明らかな脂肪肝との関与は認めなかった。また血中miR-33b*と血中HDL-Cの間には負の相関を認めた。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] MicroRNAs and lipoprotein metabolism. (2014)
  • Author(s): 1: Horie-T, Baba-O, Kuwabara-Y, Yokode-M, Kita-T, Kimura-T, Ono-K
  • Journal Title: J of Atherosclerosis and Thrombosis Volume: 21 Pages: 17-22
  • Peer Reviewed
• [Journal Article] Myocardial expression level of neural cell adhesion molecule correlates with reduced left ventricular function in human cardiomyopathy (2014)
  • Author(s): Nagao K, Sowa N, Inoue K, Tokunaga M, Fukuchi K, Uchiyama K, Ito H, Hayashi F, Makita T, Inada T, Tanaka M, Kimura T, and Ono K
  • Journal Title: Circulation; Heart Failur Volume: 7 Issue: 2 Pages: 351-8
  • DOI: 10.1161/circheartfailure.113.000939
  • Peer Reviewed
• [Journal Article] MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice. (2013)
  • Author(s): Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Sowa N, Yahagi N, Shimano H, Matsumura S, Inoue K, Marusawa H, Nakamura T, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, Ono K
  • Journal Title: Nat Commun. Volume: 4:2883 Issue: 1 Pages: 2883-2883
  • DOI: 10.1038/ncomms3883
  • NAID: 120005349007
  • Peer Reviewed / Open Access
• [Journal Article] Long-Term Outcomes After Percutaneous Coronary Intervention for Chronic Total Occlusion (from the CREDO-Kyoto Registry Cohort-2) (2013)
  • Author(s): 5: Yamamoto E, Natsuaki M, Morimoto T, Furukawa Y, Nakagawa Y, Ono K, Mitsudo K, Nobuyoshi M, Doi O, Tamura T, Tanaka M, Kimura T; CREDO-Kyoto PCI/CABG Registry Cohort-2 Investigators.
  • Journal Title: Am J Cardiol. Volume: １１２ Issue: 6 Pages: 767-74
  • DOI: 10.1016/j.amjcard.2013.05.004
  • Peer Reviewed
• [Journal Article] Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Plays an Important Role in Vascular Inflammation in Current Smokers. (2013)
  • Author(s): 6: Takanabe-Mori R, Ono K, Wada H, Takaya T, Ura S, Yamakage H, Satoh-Asahara N, Shimatsu A, Takahashi Y, Fujita M, Fujita Y, Sawamura T, Hasegawa K.
  • Journal Title: J Atheroscler Thromb. Volume: 20 Pages: 585-90
  • Peer Reviewed
• [Journal Article] CREDO-Kyoto PCI/CABG registry cohort-2 investigators. Impact of polyvascular disease on clinical outcomes in patients undergoing coronary revascularization : An observation from the CREDO-Kyoto Registry Cohort-2 (2013)
  • Author(s): Morikami Y, Natsuaki M, Morimoto T, Ono K, Nakagawa Y, Furukawa Y, Sakata R, Aota M, Okada Y, Onoe M, Kawasuji M, Koshiji T, Nakajima H, Nishizawa J, Yamanaka K, Yamamoto H, Kimura T
  • Journal Title: Atherosclerosis Volume: 228 Issue: 2 Pages: 426-31
  • DOI: 10.1016/j.atherosclerosis.2013.04.005
  • Peer Reviewed
• [Journal Article] Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts (2013)
  • Author(s): Tamaki Y, Iwanaga Y, Niizuma S, Kawashima T, Kato T, Inuzuka Y, Horie T, Morooka H, Takase T, Akahashi Y, Kobuke K, Ono K, Shioi T, Sheikh SP, Ambartsumian N, Lukanidin E, Koshimizu TA, Miyazaki S, Kimura T
  • Journal Title: J Mol Cell Cardiol Volume: 57 Pages: 72-81
  • DOI: 10.1016/j.yjmcc.2013.01.007
  • Peer Reviewed
• [Journal Article] Influence of initial acute myocardial infarction presentation on the outcome of surgical procedures after coronary stent implantation: a report from the CREDO-Kyoto PCI/CABG Registry Cohort-2. (2013)
  • Author(s): Tokushige A
  • Journal Title: Cardiovasc Interv Ther Volume: 28 Issue: 1 Pages: 45-55
  • DOI: 10.1007/s12928-012-0136-x
  • Peer Reviewed
• [Journal Article] MicroRNA-33-deficiency reduces the progression of atherosclerotic plaque in apoE-/- mice (2012)
  • Author(s): Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M, Horiguchi M, Nakamura T, Chonabayashi K, Hishizawa M, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, Ono K
  • Journal Title: JAm Heart Assoc Volume: 1 Issue: 6
  • DOI: 10.1161/jaha.112.003376
  • Peer Reviewed
• [Journal Article] Current concept of reverse cholesterol transport and novel strategy for atheroprotection (2012)
  • Author(s): Ono K
  • Journal Title: J Cardiol Volume: 60 Issue: 5 Pages: 339-43
  • DOI: 10.1016/j.jjcc.2012.07.014
  • NAID: 120004996385
  • Peer Reviewed
• [Journal Article] Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia (2012)
  • Author(s): N. Satoh-Asahara, A. Shimatsu, Y. Sasaki, H. Nakaoka, A. Himeno, M. Tochiya, S. Kono, T. Takaya, K. Ono, H. Wada, T. Suganami, K. Hasegawa, Y. Ogawa
  • Journal Title: Diabetes Care Volume: 35 Issue: 12 Pages: 2631-2639
  • DOI: 10.2337/dc12-0269
  • Peer Reviewed
• [Journal Article] MicroRNA 26b Encoded by the Intron of Small CTD Phosphatase (SCP) 1 Has an Antagonistic Effect on its Host Gene (2012)
  • Author(s): Sowa N, Horie T, Kuwabara Y, Baba O, Watanabe S, Nishi H, Kinoshita M, Takanabe-Mori R, Wada H, Shimatsu A, Hasegawa K, Kimura T, and Ono K
  • Journal Title: Journal ofCellular Biochem. Volume: 113 Issue: 11 Pages: 3455-65
  • DOI: 10.1002/jcb.24222
  • Peer Reviewed
• [Journal Article] α1-Antitrypsin-low-density-lipoprotein Serves as a Marker of Smoking-specific Oxidative Stress. (2012)
  • Author(s): Wada-H
  • Journal Title: J Atheroscler Thromb Volume: 19 Pages: 47-58
  • Peer Reviewed
• [Presentation] MicroRNA-451 Exacerbates Lipotoxicity in Neonatal Rat Cardiomyocytes, and High Fat Diet Induced Cardiac Hypertrophy in Mice through LKB1/AMPK Pathway. (2014)
  • Author(s): Yasuhide Kuwabara,Takahiro Horie, Osamu Baba, Shin Watanabe, Masayasu Izuhara, Tetsushi Nakao, Shunsuke Usami, Tomohiro Nishino, Masataka Nishiga, Toru Kita, Takeshi Kimura, Koh Ono
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: Tokyo
• [Presentation] Shock Reduction Strategies in High Energy Devices. (2014)
  • Author(s): Satoshi Shizuta, Takahiro Doi , Mitsuhiko Yahata , Tetsuma Kawaji , Kentaro Nakai , Hiroaki Sugiyama , Koji Goto , Takeru Makiyama , Koh Ono , Tetsuo Shioi , Takeshi Kimura
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: Tokyo
• [Presentation] MicroRNA-33 Encoded by an Intron of Sterol Regulatory Element-Binding Protein 2 (Srebp2) Regulates Srebp1 in vivo. (2014)
  • Author(s): Takahiro Horie, Tomohiro Nishino, Osamu Baba, Yasuhide Kuwabara, Tetsushi Nakao, Masataka Nishiga, Shunsuke Usami, Masayasu Izuhara, Naoya Sowa, Naoya Yahagi, Hitoshi Shimano, Masayuki Yokode, Toru Kita, Takeshi Kimura, Koh Ono
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: Tokyo
• [Presentation] Use of miRNA for the Detection of Cardiotoxicity. (2013)
  • Author(s): Ono K.
  • Organizer: 4th DIA Cardiac Safety Workshop in Japan
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] Cardiac-specific inhibition of kinase activity in calcium/calmodulin-dependent kinase kinase- leads to accerelated left ventricular remodeling and heart failure after transverse aortic constriction in mice. (2013)
  • Author(s): Ono K.
  • Organizer: Cold spring harbor laboratory meeting.
  • Place of Presentation: NY, U.S.A.
• [Presentation] MicroRNA encoded by an intron of Srebf2 regulates SREBP-1 in vivo. (2013)
  • Author(s): Koh Ono
  • Organizer: 平成25年度新学術領域「転写代謝システム」第5回総括班会議
  • Place of Presentation: 兵庫
• [Presentation] LncRNAs regulated by pressure-overload induce hypertrophy in neonatal mouse ventricular cardiomyocytes. (2013)
  • Author(s): Kuwabara Y.
  • Organizer: American Heart Association Annual Scientific Sessions 2013
  • Place of Presentation: Dallas, U.S.A.
• [Presentation] マイクロRNA-33欠損はアポE欠損マウスにおいて動脈硬化形成を抑制する (2013)
  • Author(s): 堀江貴裕、馬場 理、木村 剛、尾野 亘
  • Organizer: 第50回日本臨床分子医学会学術集会
  • Place of Presentation: 東京
• [Presentation] HDLコレステロール仮説に関する最近の話題 (2013)
  • Author(s): 尾野 亘
  • Organizer: 第115回日本循環器学会近畿地方会
  • Place of Presentation: 京都
  • Invited
• [Presentation] MicroRNA-33 Deficiency Reduces the Progressio of Atherosclerotic Plaque in ApoE-/- Mice (2013)
  • Author(s): 堀江貴裕、馬場 理、木村 剛、尾野 亘
  • Organizer: 第45回日本動脈硬化学会
  • Place of Presentation: 東京
• [Presentation] マイクロRNAのバイオマーカーとしての応用 (2013)
  • Author(s): 尾野 亘
  • Organizer: 第45回日本動脈硬化学会 シンポジウム４
  • Place of Presentation: 東京
  • Invited
• [Presentation] miRNAを介した生体における転写環境と代謝の関連の検討 (2013)
  • Author(s): 尾野 亘
  • Organizer: 平成25年度新学術領域「転写代謝システム」第5回総括班会議
  • Place of Presentation: 兵庫
• [Presentation] microRNAと動脈硬化・心不全 (2013)
  • Author(s): 尾野 亘
  • Organizer: 第23回 循環薬理学会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] MicroRNA 33 Deficiency in Leukocytes Reduced the Lipid Accumulation in Atherosclerotic Plaque in ApoE Knockout Mice. (2012)
  • Author(s): Baba-O
  • Organizer: American Heart Association Annual Scientific Sessions 2012
  • Place of Presentation: Los Angeles Convention Center, LA, USA
  • Year and Date: 2012-11-03
• [Presentation] MicroRNA-33 Deficiency Reduced Atherosclerosis Formation In Vivo. (2012)
  • Author(s): Horie-T
  • Organizer: American Heart Association Annual Scientific Sessions 2012
  • Place of Presentation: Los Angeles Convention Center, LA, USA
  • Year and Date: 2012-11-03
• [Presentation] MicroRNA-33-deficiency reduces the progression of atherosclerotic plaque in apoE-/- mice (2012)
  • Author(s): Ono-K
  • Organizer: Cold spring harbor laboratory meeting. Regulatory and non-coding RNA
  • Place of Presentation: Cold spring harbor laboratory, NY, USA
  • Year and Date: 2012-08-28
• [Presentation] MicroRNA 33 Deficiency Reduces Atherosclerotic Plaque progression in ApoE Knockout Mice. (2012)
  • Author(s): Baba-O
  • Organizer: European Society of Cardiology Congress 2012
  • Place of Presentation: Internationales Congress Center Munchen, Munich、Germany
  • Year and Date: 2012-08-25
• [Presentation] Interaction of S100A4 with p53 in fibroblasts modulates cardiac fibrosis through two distinct mechanisms. (2012)
  • Author(s): Tamaki-Y
  • Organizer: European Society of Cardiology Congress 2012
  • Place of Presentation: Internationales Congress Center Munchen, Munich、Germany
  • Year and Date: 2012-08-25
• [Presentation] MicroRNA regulation of lipid homeostasis. (2012)
  • Author(s): Ono-K
  • Organizer: 25th Spring Congress of Korean Diabetes Association
  • Place of Presentation: Hotel Inter-Burgo, Daegu、Korea
  • Invited
• [Book] Annual Review 循環器2014 (2014)
  • Author(s): 尾野 亘
  • Total Pages: 315
  • Publisher: 中外医学社
• [Book] 細胞工学 疾患エクソソーム (2013)
  • Author(s): 尾野 亘
  • Publisher: 秀潤社
• [Book] Annual Review 糖尿病・代謝・内分泌2012 (2012)
  • Author(s): 尾野 亘
  • Publisher: 中外医学社
• [Remarks] 心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Remarks] 尾野 亘 講師らの成果が、Nature Communicationsに掲載されました
  • URL: http://tmsystem.tara.tsukuba.ac.jp/?p=2424
• [Remarks] 京都大学大学院医学研究科循環器内科心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Patent(Industrial Property Rights)] マイクロＲＮＡ溶出型ステント及びそれを用いた管腔治療 (2014)
  • Inventor(s): 尾野 亘、斉藤成達、木村 剛、出原正康
  • Industrial Property Rights Holder: 尾野 亘、斉藤成達、木村 剛、出原正康
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-044463
  • Filing Date: 2014-03-07
• [Patent(Industrial Property Rights)] 大動脈瘤および大血管の炎症抑制治療製剤 (2012)
  • Inventor(s): 尾野 亘
  • Industrial Property Rights Holder: 尾野 亘
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-10-31
  • Overseas