Elucidation of the functions of miR-33a/b in cholesterol homeostasis

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390211
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto University
• Principal Investigator: ONO KOH 京都大学, 医学(系)研究科(研究院), 講師 (00359275)
• Co-Investigator(Kenkyū-buntansha): NAKAMURA Tomoyuki 関西医科大学, 医学部薬理学 (20362527)
• Co-Investigator(Renkei-kenkyūsha): KAKEYA Hideaki 京都大学, 大学院・薬学研究科 (00270596) ; SATO Fumiaki 京都大学, 大学院・薬学研究科 (20467426) ; HORIE Takahiro 京都大学, 大学院・医学研究科循環器内科 (20565577)
• Project Period (FY): 2011-11-18 – 2014-03-31
• Keywords: マイクロRNA / HDL-C / 動脈硬化 / ABCA1 / SREBP-2 / SREBP-1 / 脂肪肝

Research Abstract

MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, have indicated that miR-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here we show that deletion of miR-33 results in marked worsening of high fat diet-induced obesity and liver steatosis. Using miR-33-/-Srebf1+/- mice we demonstrate that SREBP-1 is a target of miR-33 and that the mechanisms leading to obesity and liver steatosis in miR-33-/- mice involve enhanced expression of SREBP-1. These results elucidate a novel interaction between SREBP-1 and SREBP-2 mediated by miR-33 in vivo.

Research Products

• [Journal Article] MicroRNAs and lipoprotein metabolism (2014)
  • Author(s): Horie T, Baba O, Kuwabara Y, Yokode M, Kita T, Kimura T, and Ono K
  • Journal Title: J of Atherosclerosis and Thrombosis Volume: 21 Pages: 17-22
  • URL: https://www.jstage.jst.go.jp/article/jat/21/1/21_20859/_article
  • 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 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, and Ono K
  • Journal Title: Nat Commun Volume: 4 Pages: 2883
  • DOI: 10.1038/ncomms3883
  • 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 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] 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 Pages: e003376
  • 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 Pages: 339-43
  • DOI: 10.1016/j.jjcc.2012.07.014
  • 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 Pages: 3455-65
  • DOI: 10.1002/jcb.24222
  • Peer Reviewed
• [Journal Article] Increased microRNA-1 and microRNA-133a Levels in Serum of Patients with Cardiovascular Disease Indicate the Existence of Myocardial Damage (2011)
  • Author(s): Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Kinoshita M, Watanabe S, Baba O, Kojima Y, Shizuta S, Imai M, Tamura T, Kita T, Kimura T
  • Journal Title: Circulation : Cardiovascular Genetics Volume: 4 Pages: 446-454
  • DOI: 10.1161/CIRCGENETICS.110.958975
  • Peer Reviewed
• [Journal Article] MicroRNA links obesity and impaired glucose metabolism (2011)
  • Author(s): Ono K
  • Journal Title: Cell Res Volume: 21 Pages: 864-6
  • DOI: 10.1038/cr.2011.78
  • Peer Reviewed
• [Journal Article] MicroRNAs and Cardiovascular Diseases (2011)
  • Author(s): Ono K, Kuwabara Y, Han J
  • Journal Title: FEBS J Volume: 278 Pages: 1619-33
  • DOI: 10.1111/j.1742-4658.2011.08090.x
  • Peer Reviewed
• [Journal Article] Comparison of Three-Year Clinical Outcomes after Sirolimus-eluting Stent Implantation among Insulin-treated Diabetic, Non-insulin-treated Diabetic and Non-diabetic Patients From the j-Cypher Registry (2011)
  • Author(s): Tada T, Kimura T, Morimoto T, Ono K, Furukawa Y, Nakagawa Y, Nakashima H, Ito A, Shiode N, Namura M, Inoue N, Nishikawa H, Nakao K, Mitsudo K
  • Journal Title: Am J Cardiol Volume: 107 Pages: 1155-62
  • DOI: 10.1016/j.amjcard.2010.12.013
  • Peer Reviewed
• [Journal Article] MicroRNA-27a regulates beta cardiac myosin heavy chain gene expression by targeting thyroid hormone receptor beta 1 in neonatal rat ventricular myocytes (2011)
  • Author(s): Nishi H, Ono K, Horie T, Nagao K, Kinoshita M, Kuwabara Y, Watanabe S, Takaya T, Tamaki Y, Takanabe-Mori R, Wada H, Hasegawa K, Iwanaga Y, Kawamura T, Kita T, Kimura T
  • Journal Title: Mol Cell Biol Volume: 31 Pages: 744-55
  • DOI: 10.1128/MCB.00581-10
  • Peer Reviewed
• [Presentation] MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein-2 (Srebp2) regulates Srebp1 in vivo (2014)
  • Author(s): Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Sowa N, Yahagi N, Shimano H, Hasegawa K, Kume N Yokode M, Kita T, Kimura T, Ono K
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14
• [Presentation] Cholesterol and Fatty acid regulation by miR-33a/b (2014)
  • Author(s): Ono K
  • Organizer: Molecular Clock ~New waves of RNA regulation~
  • Place of Presentation: Kyoto
  • Year and Date: 2014-03-29
• [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
  • Place of Presentation: Dallas
  • Year and Date: 20131116-22
• [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
  • Year and Date: 20130813-17
• [Presentation] MicroRNA-33 Deficiency Reduced Atherosclerosis Formation In Vivo (2012)
  • Author(s): Horie T, Baba O, Ono K, Kuwabara Y, Hasegawa K, Kume N, Yokode M, Kita T, and Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions 2012
  • Place of Presentation: Los Angeles Convention Center
  • Year and Date: 20121103-07
• [Presentation] MicroRNA-33-deficiency reduces the progression of atherosclerotic plaque in apoE-/- mice Cold spring harbor laboratory meeting (2012)
  • Author(s): Ono K
  • Organizer: Regulatory and non-coding RNA
  • Place of Presentation: NY, U.S.A
  • Year and Date: 20120828-0901
• [Presentation] MicroRNA 33 Deficiency Reduces Atherosclerotic Plaque progression in ApoE Knockout Mice (2012)
  • Author(s): Baba O, Horie T, Nakamura T, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, and Ono K
  • Organizer: European Society of Cardiology Congress 2012
  • Place of Presentation: Munich - Germany
  • Year and Date: 20120825-29
• [Presentation] Symposium 6 (Insulin resistance) MicroRNA regulation of lipid homeostasis (2012)
  • Author(s): Ono K
  • Organizer: 25th Spring Congress of Korean Diabetes Association
  • Place of Presentation: Hotel Inter-Burgo Exco, Daegu
  • Year and Date: 2012-05-11
• [Presentation] MicroRNA-1 and microRNA-133a elevations in serum of patients with cardiovascular disease indicate the existence of myocardial damage (2011)
  • Author(s): Kuwabara Y, Ono K, Horie T, Nishi H, Watanabe S, Kinoshita M, Baba O, Chujo Y, Nagao K, Kojima Y, Kita T, Kimura T
  • Organizer: American Heart Association Annual Scientific Sessions
  • Place of Presentation: Orlando, Florida
  • Year and Date: 20111112-16
• [Presentation] Neural cell adhesion molecule is a cardioprotective factor upregulated by metabolic stress (2011)
  • Author(s): Nagao K, Ono K, Horie T, Tamaki Y, Iwanaga Y, Makita T, Inada T, Tanaka M, Kita T, Kimura T
  • Organizer: European Society of Cardiology Congress
  • Place of Presentation: Paris, France
  • Year and Date: 20110827-31
• [Presentation] MicroRNA-33 Encoded by an Intron of Srebp2 Regulates HDL in vivo. 2011AVDRC International Symposium (2011)
  • Author(s): Ono K
  • Organizer: Intervention of Vascular Aging : New Frontiers
  • Place of Presentation: College of Medicine, Yeungnam University, Daegu, Korea
  • Year and Date: 2011-09-22
• [Book] Annual Review循環器2014, 代謝と循環器疾患に関わるmicroRNA (2014)
  • Author(s): 尾野亘
  • Total Pages: 35-41
  • Publisher: 中外医学社
• [Book] Annual Review 糖尿病・代謝・内分泌2012, microRNAによるHDL代謝調節 (2012)
  • Author(s): 尾野亘
  • Total Pages: 80-85
  • Publisher: 中外医学社
• [Remarks]
  • 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, 出原正康, 木村剛
  • Industrial Property Rights Holder: 尾野亘, 斉藤成達, 出原正康, 木村剛
  • Industrial Property Number: 特願 2014-044463
  • Filing Date: 2014-03-07