Elucidation of the regulatory mechanism of lipid metabolism by intronic microRNA-33a, -33b

• Project/Area Number: 26461144
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: HORIE TAKAHIRO 京都大学, 医学研究科, 助教 (20565577)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脂質代謝 / マイクロRNA / SREBP / 動脈硬化

Outline of Final Research Achievements

miR-33a is located in the intron of SREBP2, which is a main transcriptional factor that regulates cholesterol homeostasis. On the other hand, miR-33b is located in the intron of SREBP1, which regulates fatty acid homeostasis in human. To elucidate the function of miR-33a in various organs or cells, we developed miR-33a conditional KO mice. When miR-33a was ablated in fibroblast cells, cardiac fibrosis was inhibited under pressure-overload condition via modulation of lipid rafts. To elucidate the function of miR-33b in vivo, we developed miR-33b knock-in mice, which have human miR-33b sequence in the same intron of SREBP1 as human. These mice showed reduced expression of ABCA1 and decreased levels of serum HDL-C. These results indicate that miR-33a/b have multiple functions in regulating lipid homeostasis.

Research Products

• [Journal Article] Prevention of neointimal formation using miRNA-126-containing nanoparticle-conjugated stents in a rabbit model. (2017)
  • Author(s): Izuhara M, Kuwabara Y, Saito N, Yamamoto E, Hakuno D, Nakashima Y, Horie T, Baba O, Nishiga M, Nakao T, Nishino T, Nakazeki F, Ide Y, Kimura M, Kimura T, Ono K.
  • Journal Title: PLoS One Volume: 12(3) Issue: 3 Pages: e0172798-e0172798
  • DOI: 10.1371/journal.pone.0172798
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. (2016)
  • Author(s): Nishiga M, Horie T, Kuwabara Y, Nagao K, Baba O, Nakao T, Nishino T, Hakuno D, Nakashima Y, Nishi H, Nakazeki F, Ide Y, Koyama S, Kimura M, Hanada R, Nakamura T, Inada T, Hasegawa K, Conway SJ, Kita T, Kimura T, Ono K.
  • Journal Title: Circ Res. Volume: - Issue: 5 Pages: 835-847
  • DOI: 10.1161/circresaha.116.309528
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development. (2016)
  • Author(s): Eso Y, Takai A, Matsumoto T, Inuzuka T, Horie T, Ono K, Uemoto S, Lee K, Edelmann W, Chiba T, Marusawa H.
  • Journal Title: Cancer Research Volume: 76 Issue: 15 Pages: 4383-93
  • DOI: 10.1158/0008-5472.can-15-2926
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Emerging Novel Biomarkers for Arteriosclerosis Obliterans (2016)
  • Author(s): Horie T, Kimura T, Ono K.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 23 Issue: 2 Pages: 171-172
  • DOI: 10.5551/jat.ED028
  • NAID: 130005122030
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Expression Patterns of miRNA-423-5p in the Serum and Pericardial Fluid in Patients Undergoing Cardiac Surgery. (2015)
  • Author(s): Miyamoto S, Usami S, Kuwabara Y, Horie T, Baba O, Hakuno D, Nakashima Y, Nishiga M, Izuhara M, Nakao T, Nishino T, Ide Y, Nakazeki F, Wang J, Ueyama K, Kimura T, Ono K.
  • Journal Title: PLoS One. Volume: 10(11) Issue: 11 Pages: e0142904-e0142904
  • DOI: 10.1371/journal.pone.0142904
  • NAID: 120005749912
  • Peer Reviewed / Open Access
• [Journal Article] microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain. (2015)
  • Author(s): Kim J, Yoon H, Horie T, Burchett JM, Restivo JL, Rotllan N, Ramírez CM, Verghese PB, Ihara M, Hoe HS, Esau C, Fernández-Hernando C, Holtzman DM, Cirrito JR, Ono K, Kim J.
  • Journal Title: J Neurosci. Volume: 35(44) Issue: 44 Pages: 14717-26
  • DOI: 10.1523/jneurosci.2053-15.2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNAs and High-Density Lipoprotein Cholesterol Metabolism (2015)
  • Author(s): Ono K, Horie T, Nishino T, Baba O, Kuwabara Y, Kimura T.
  • Journal Title: International Heart Journal Volume: 56 Issue: 4 Pages: 365-371
  • DOI: 10.1536/ihj.15-019
  • NAID: 130005087574
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] High-density lipoprotein cholesterol levels and cardiovascular outcomes in Japanese patients after percutaneous coronary intervention: a report from the CREDO-Kyoto registry cohort-2. (2015)
  • Author(s): Izuhara M, Ono K, Shiomi H, Morimoto T, Furukawa Y, Nakagawa Y, Shizuta S, Tada T, Tazaki J, Horie T, Kuwabara Y, Baba O, Nishino T, Kita T, Kimura T; CREDO-Kyoto PCI/CABG Registry Cohort-2 Investigators.
  • Journal Title: Atherosclerosis. Volume: 242(2) Issue: 2 Pages: 632-8
  • DOI: 10.1016/j.atherosclerosis.2015.05.010
  • NAID: 120005678183
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33a/b in Lipid Metabolism (2015)
  • Author(s): Ono K, Horie T, Nishino T, Baba O, Kuwabara Y, Yokode M, Kita T, Kimura T.
  • Journal Title: Circulation Journal Volume: 79 Issue: 2 Pages: 278-284
  • DOI: 10.1253/circj.CJ-14-1252
  • NAID: 130004927073
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. (2015)
  • Author(s): Kuwabara Y, Horie T, Baba O, Watanabe S, Nishiga M, Usami S, Izuhara M, Nakao T, Nishino T, Otsu K, Kita T, Kimura T, Ono K.
  • Journal Title: Circulation Research Volume: 116 Issue: 2 Pages: 279-288
  • DOI: 10.1161/circresaha.116.304707
  • Peer Reviewed
• [Journal Article] MicroRNAs and lipoprotein metabolism. (2014)
  • Author(s): Horie-T, Baba-O, Kuwabara-Y, Yokode-M, Kita-T, Kimura-T, Ono-K
  • Journal Title: J Atheroscler Thromb Volume: 21 Pages: 17-22
  • NAID: 130004845461
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo. (2014)
  • Author(s): Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Nakazeki F, Ide Y, Koyama S, Sowa N, Yahagi N, Shimano H, Nakamura T, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, Ono K.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 5312-5312
  • DOI: 10.1038/srep05312
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac-Specific Inhibition of Kinase Activity in Calcium/Calmodulin-Dependent Protein Kinase Kinase-β Leads to Accelerated Left Ventricular Remodeling and Heart Failure after Transverse Aortic Constriction in Mice (2014)
  • Author(s): Shin Watanabe, Takahiro Horie, Kazuya Nagao, Yasuhide Kuwabara, Osamu Baba, Hitoo Nishi, Naoya Sowa, Michiko Narazaki, Tetsuya Matsuda, Genzou Takemura, Hiromichi Wada, Koji Hasegawa, Takeshi Kimura, Koh Ono
  • Journal Title: PLoS ONE Volume: 9 Issue: 9 Pages: e108201-e108201
  • DOI: 10.1371/journal.pone.0108201
  • NAID: 120005496630
  • Peer Reviewed / Open Access
• [Presentation] MicroRNA-33 Promotes Cardiac Fibrosis Through Maintaining Cellular Lpid Contents. (2016)
  • Author(s): Nishiga M, Horie T, Kuwabara Y, Nakao K, Kimura T, Ono K.
  • Organizer: 第20回 日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-07
• [Presentation] Overexpression of the LincRNA Regulated by Pressure-Overload Leads to Cardiomyocyte Hypertrophy. (2016)
  • Author(s): Kuwabara Y, Horie T, Baba O, Nishiga M, Nakao M, Nishino T, Nakazeki F, Koyama S, Kimura T, Ono K.
  • Organizer: 第20回 日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-07
• [Presentation] Changes and Physiological Meanings of Serum microRNA during Therapeutic Course of Acute Heart Failure. (2016)
  • Author(s): Koyama S, Kuragaichi T, Sato Y, Kuwabara Y, Horie T, Baba O, Kimura T, Ono K.
  • Organizer: 第20回 日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-07
• [Presentation] マイクロＲＮＡによるHDL代謝制御 (2016)
  • Author(s): 堀江貴裕
  • Organizer: 第48回 日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-07-14
  • Invited
• [Presentation] マイクロRNA-33を介した新たな脂質代謝制御機構の解明 (2016)
  • Author(s): 堀江貴裕、西野共達、馬場理、桑原康秀、木村剛、尾野亘
  • Organizer: 第45回日本心脈管作動物質学会
  • Place of Presentation: 徳島
  • Year and Date: 2016-02-05
  • Invited
• [Presentation] Srebp1のイントロンに存在するmicroRNA-33bはHDLコレステロールを減少させる (2015)
  • Author(s): 堀江貴裕、西野共達、馬場理、桑原康秀、中尾哲史、西賀雅隆、宇佐美俊輔、出原正康、中関典子、井手裕也、小山智史、曽和尚也、矢作直也、島野仁、横出正之、北徹、木村剛、尾野亘
  • Organizer: 第23回日本血管生物医学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-10
• [Presentation] Serum HDL Cholesterol decreases in microRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1). (2015)
  • Author(s): Takahiro Horie, Tomohiro Nishino, Osamu Baba, Yasuhide Kuwabara, Tetsushi Nakao, Masataka Nishiga, Shunsuke Usami, Masayasu Izuhara, Fumiko Nakazeki, Yuya Ide, Satoshi Koyama, Naoya Sowa, Yasuhiro Nakashima, Daihiko Hakuno, Takeshi Kimura, Koh Ono
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: Orlando, FL
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Serum HDL-C decreases in microRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1). (2015)
  • Author(s): Takahiro Horie, Tomohiro Nishino, Yasuhide Kuwabara, Osamu Baba, Takeshi Kimura, Koh Ono
  • Organizer: Basic Cardiovascular Sciences Scientific Sessions 2015
  • Place of Presentation: New Orleans, LA
  • Year and Date: 2015-07-13
  • Int'l Joint Research
• [Presentation] Srebf1のイントロンにmicroRNA-33bをノックインしたマウスはHDLコレステロールの減少を示す (2015)
  • Author(s): 堀江貴裕、西野共達、馬場理、桑原康秀、中尾哲史、西賀雅隆、宇佐美俊輔、出原正康、中関典子、井手裕也、小山智史、曽和尚也、矢作直也、島野仁、横出正之、北徹、木村剛、尾野亘
  • Organizer: 第47回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2015-07-09
• [Presentation] Srebp1のイントロンに存在するmicroRNA-33bはHDLコレステロールを減少させる (2015)
  • Author(s): 堀江貴裕、西野共達、馬場理、桑原康秀、中尾哲史、西賀雅隆、宇佐美俊輔、出原正康、中関典子、井手裕也、小山智史、曽和尚也、矢作直也、島野仁、横出正之、北徹、木村剛、尾野亘
  • Organizer: 第１回国際心血管薬物療法学会日本部会
  • Place of Presentation: 京都
  • Year and Date: 2015-06-20
• [Presentation] Srebf1のイントロンにmicroRNA-33bをノックインしたマウスはHDLコレステロールの減少を示す。 (2015)
  • Author(s): 堀江貴裕、西野共達、馬場理、桑原康秀、中尾哲史、西賀雅隆、宇佐美俊輔、出原正康、中関典子、井手裕也、小山智史、曽和尚也、矢作直也、島野仁、横出正之、北徹、木村剛、尾野亘
  • Organizer: 若手ワークショップ＠伊香保（転写研究会＆転写サイクル＆転写代謝システム共催）
  • Place of Presentation: 群馬
  • Year and Date: 2015-02-05 – 2015-02-07
• [Presentation] 心血管代謝疾患形成に関与するマイクロRNAの機能解析 (2014)
  • Author(s): 堀江貴裕
  • Organizer: 第50回高血圧モデル学会学術総会
  • Place of Presentation: 和歌山
  • Year and Date: 2014-12-05 – 2014-12-06
  • Invited
• [Presentation] Srebf1のイントロンにmicroRNA-33bをノックインしたマウスはHDLコレステロールの減少を示す。 (2014)
  • Author(s): 堀江貴裕、西野共達、馬場理、桑原康秀、中尾哲史、西賀雅隆、宇佐美俊輔、出原正康、井手裕也、中関典子、小山智史、曽和尚也、木村剛、尾野亘
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] MicroRNA-33b Knock-in Mice for an Intron of Sterol Regulatory Element-Binding Factor 1 (Srebf1) Exhibit Reduced HDL-C in vivo. (2014)
  • Author(s): Takahiro Horie, Tomohiro Nishino, Osamu Baba, Yasuhide Kuwabara, Tetsushi Nakao, Masataka Nishiga, Shunsuke Usami, Masayasu Izuhara, Fumiko Nakazeki, Yuya Ide, Satoshi Koyama, Masayuki Yokode, Takeshi Kimura, and Koh Ono
  • Organizer: American Heart Association 2014 Scientific Sessions
  • Place of Presentation: USA, Chicago
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Serum HDL-C decreases in microRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor (Srebf1). (2014)
  • Author(s): Takahiro Horie, Tomohiro, Nishino, Osamu Baba, Yasuhide Kuwabara, Tetsushi Nakao, Masataka Nishiga, Shunsuke Usami, Masayasu Izuhara, Takeshi Kimura, Koh Ono
  • Organizer: 9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress (MSDA)
  • Place of Presentation: Japan, Kyoto
  • Year and Date: 2014-09-12 – 2014-09-14
• [Presentation] MicroRNA-33 deficiency leads to high fat diet- induced obesity and insulin resistance in vivo. (2014)
  • Author(s): Takahiro Horie, Tomohiro Nishino, Osamu Baba, Yasuhide Kuwabara, Tetsushi Nakao, Masataka Nishiga, Shunsuke Usami, Masayasu Izuhara, Naoya Sowa, Takeshi Kimura, and Koh Ono
  • Organizer: European Society of Cardiology Congress 2014
  • Place of Presentation: Spain, Barcelona
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] マイクロRNA-33による脂質代謝制御機構の解明 (2014)
  • Author(s): 堀江貴裕
  • Organizer: 第46回 日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-11
  • Invited
• [Presentation] SREBP-2のイントロンに存在するマイクロRNA-33はSREBP-1の発現を制御する。 (2014)
  • Author(s): 堀江貴裕
  • Organizer: Research PlaNet 2014
  • Place of Presentation: 東京
  • Year and Date: 2014-05-10 – 2014-05-11
• [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, Koji Hasegawa, Noriaki Kume, Masayuki Yokode, Toru Kita, Takeshi Kimura, Koh Ono
  • Organizer: The 18th International Vascular Biology Meeting (IVBM)
  • Place of Presentation: Japan, Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] SREBP-2のイントロンに存在するマイクロRNA-33はSREBP-1の発現を制御する。 (2014)
  • Author(s): 堀江貴裕、西野共達、馬場理、桑原康秀、矢作直也、島野仁、横出正之、北徹、木村剛、尾野亘
  • Organizer: 第51回日本臨床分子医学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-11 – 2014-04-12
• [Remarks] 京都大学循環器内科 心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Remarks] 京都大学医学部附属病院循環器内科 心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/