Investigation of the role of microRNAs in the formation of liver fibrosis

• Project/Area Number: 17K09860
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: Takahiro Horie 京都大学, 医学研究科, 助教 (20565577)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 非アルコール性脂肪肝炎 / 非コードRNA / マイクロRNA / コレステロール / 脂肪酸 / NASH / SREBP / microRNA / 治療応用 / 内科 / 脂質 / トランスレーショナルリサーチ

Outline of Final Research Achievements

The number of patients with non-alcoholic steatohepatitis is glowing with the westernization of life in our country. Although progression from non-alcoholic steatohepatitis to the development of liver cirrhosis and liver cancer is a concerning issue, the cause has not been clarified and the treatment has not been established. In this study, we investigated the role of microRNAs, a small non-coding RNA that is not translated into proteins of about, in the formation of non-alcoholic steatohepatitis. It became clear that microRNAs could have important roles in the development of non-alcoholic steatohepatitis.

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪肝炎は脂肪肝の患者の1割程度に見られる、肝臓の炎症と線維化を主体とする肝炎である。この病態が進行すると肝硬変、肝がんなどへつながることが示されているが、その成因が明らかでなく根本治療法はない。近年、蛋白にならない遺伝子として非コードRNAに注目が集まっている。本研究から非コードRNAの一つであるマイクロRNAがその成因に大きな役割を果たしていることが明らかとなった。マイクロRNAの発現や機能を制御することが新たな治療法の開発につながると考えられる。

Research Products

• [Journal Article] ABLE-MET Investigators. Effects of Metformin on Left Ventricular Size and Function in Hypertensive Patients with Type 2 Diabetes Mellitus: Results of a Randomized, Controlled, Multicenter, Phase IV Trial. (2020)
  • Author(s): Ono K, Wada H, Satoh-Asahara N, Inoue H, Uehara K, Funada J, Ogo A, Horie T, Fujita M, Shimatsu A, Hasegawa K.
  • Journal Title: Am J Cardiovasc Drugs. Volume: 20 Issue: 3 Pages: 283-293
  • DOI: 10.1007/s40256-019-00381-1
  • Peer Reviewed
• [Journal Article] MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons (2019)
  • Author(s): Nakazeki F、Tsuge I、Horie T、Imamura K、Tsukita K、Hotta A、Baba O、Kuwabara Y、Nishino T、Nakao T、Nishiga M、Nishi H、Nakashima Y、Ide Y、Koyama S、Kimura M、Tsuji S、Naitoh M、Suzuki S、Izumi Y、Kawarai T、Kaji R、Kimura T、Inoue H、Ono K
  • Journal Title: Clinical Science Volume: 133 Issue: 4 Pages: 583-595
  • DOI: 10.1042/cs20180980
  • NAID: 120006937614
  • Peer Reviewed / Open Access
• [Journal Article] The identification of differential roles of microRNA-33a and -33b during atherosclerosis progression with genetically modified mice. (2019)
  • Author(s): Koyama S, Horie T, Nishino T, Baba O, Sowa N, Miyasaka Y, Kuwabara Y, Nakao T, Nishiga M, Nishi H, Nakashima Y, Nakazeki F, Ide Y, Kimura M, Tsuji S, Rodriguez RR, Xu S, Yamasaki T, Otani C, Watanabe T, Nakamura T, Hasegawa K, Kimura T, Ono K.
  • Journal Title: J Am Heart Assoc. Volume: 8(13) Issue: 13
  • DOI: 10.1161/jaha.119.012609
  • NAID: 120006818702
  • Peer Reviewed / Open Access
• [Journal Article] Cardioprotective Effects of VCP?Modulator KUS121 in Murine and Porcine Models of Myocardial Infarction (2019)
  • Author(s): Ide Yuya, at al.
  • Journal Title: JACC: Basic to Translational Science Volume: 4 Issue: 6 Pages: 701-714
  • DOI: 10.1016/j.jacbts.2019.06.001
  • NAID: 120006734885
  • Peer Reviewed / Open Access
• [Journal Article] Hepatokine α1-Microglobulin Signaling Exacerbates Inflammation and Disturbs Fibrotic Repair in Mouse Myocardial Infarction (2018)
  • Author(s): Hakuno Daihiko、Kimura Masahiro、Ito Shinji、Satoh Junko、Nakashima Yasuhiro、Horie Takahiro、Kuwabara Yasuhide、Nishiga Masataka、Ide Yuya、Baba Osamu、Nishi Hitoo、Nakao Tetsushi、Nishino Tomohiro、Nakazeki Fumiko、Koyama Satoshi、Hanada Ritsuko、Randolph Ruiz R.、Endo Jin、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1-17
  • DOI: 10.1038/s41598-018-35194-w
  • NAID: 120006645320
  • Peer Reviewed / Open Access
• [Journal Article] SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo (2018)
  • Author(s): Nishino T、Horie T、Baba O、Sowa N、Hanada R、Kuwabara Y、Nakao T、Nishiga M、Nishi H、Nakashima Y、Nakazeki F、Ide Y、Koyama S、Kimura M、Nagata M、Yoshida K、Takagi Y、Nakamura T、Hasegawa K、Miyamoto S、Kimura T、Ono K.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 38 Issue: 10 Pages: 2460-2473
  • DOI: 10.1161/atvbaha.118.311409
  • Peer Reviewed / Open Access
• [Journal Article] Circulating markers of collagen types I, III, and IV in patients with dilated cardiomyopathy: relationships with myocardial collagen expression (2018)
  • Author(s): Nagao Kazuya、Inada Tsukasa、Tamura Akinori、Kajitani Kenji、Shimamura Kiyotaka、Yukawa Hiroshi、Aida Kenji、Sowa Naoya、Nishiga Masataka、Horie Takahiro、Makita Toshinori、Ono Koh、Tanaka Masaru
  • Journal Title: ESC Heart Failure Volume: 5 Issue: 6 Pages: 1044-1051
  • DOI: 10.1002/ehf2.12360
  • Peer Reviewed / Open Access
• [Journal Article] Loss of periostin ameliorates adipose tissue inflammation and fibrosis in vivo (2018)
  • Author(s): Nakazeki Fumiko、Nishiga Masataka、Horie Takahiro、Nishi Hitoo、Nakashima Yasuhiro、Baba Osamu、Kuwabara Yasuhide、Nishino Tomohiro、Nakao Tetsushi、Ide Yuya、Koyama Satoshi、Kimura Masahiro、Tsuji Shuhei、Sowa Naoya、Yoshida Shigeo、Conway Simon J.、Yanagita Motoko、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8553-8553
  • DOI: 10.1038/s41598-018-27009-9
  • NAID: 120006510274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-33 regulates the population of peripheral inflammatory Ly6Chigh monocytes through dual pathways. (2018)
  • Author(s): Baba O, Horie T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nakao T, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and Ono K.
  • Journal Title: Mol Cell Biol. Volume: 38 Issue: 14 Pages: 1-17
  • DOI: 10.1128/mcb.00604-17
  • Peer Reviewed / Open Access
• [Journal Article] Long Non-Coding RNAs as Key Regulators of Cardiovascular Diseases (2018)
  • Author(s): Ono K, Kuwabara Y, Horie T, Kimura T.
  • Journal Title: Circulation Journal Volume: 82 Issue: 5 Pages: 1231-1236
  • DOI: 10.1253/circj.CJ-18-0169
  • NAID: 130006725985
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [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] Dynamic changes of serum microRNA-122-5p through therapeutic courses indicates amelioration of acute liver injury accompanied by acute cardiac decompensation. (2017)
  • Author(s): Satoshi Koyama, Takashi Kuragaichi, Yukihito Sato, Yasuhide Kuwabara, Shunsuke Usami, Takahiro Horie, Osamu Baba, Daihiko Hakuno, Yasuhiro Nakashima, Tomohiro Nishino, Masataka Nishiga, Tetsushi Nakao, Hidenori Arai, Takeshi Kimura, Koh Ono
  • Journal Title: ESC Heart Failure Volume: 4 Issue: 2 Pages: 112-121
  • DOI: 10.1002/ehf2.12123
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways. (2017)
  • Author(s): Nakao T, Horie T, Baba O, Nishiga M, Nishino T, Izuhara M, Kuwabara Y, Nishi H, Usami S, Nakazeki F, Ide Y, Koyama S, Kimura M, Sowa N, Ohno S, Aoki H, Hasegawa K, Sakamoto K, Minatoya K, Kimura T, Ono K.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 37 Issue: 11 Pages: 2161-2170
  • DOI: 10.1161/atvbaha.117.309768
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of <i>SCN5A</i>-D1275N-Related Cardiac Sodium Channelopathy (2017)
  • Author(s): Hayano M, Makiyama T
  • Journal Title: Circulation Journal Volume: 81 Issue: 12 Pages: 1783-1791
  • DOI: 10.1253/circj.CJ-17-0064
  • NAID: 130006219109
  • ISSN: 1346-9843, 1347-4820
  • 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
• [Presentation] MiR-33a は、SPG4 遺伝性痙性対麻痺における新規治療標的である (2019)
  • Author(s): 堀江貴裕、中関典子、津下到、今村恵子、木村剛、井上治久、尾野亘
  • Organizer: 第56回日本臨床分子医学会学術集会
• [Presentation] MiR-33a/b are a novel therapeutical target for vascular disease. (2019)
  • Author(s): Takahiro Horie, Takeshi Kimura, Koh Ono
  • Organizer: 第51回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] The identification of differential roles of microRNA-33a and -33b during atherosclerosis progression with genetically modified mice. (2019)
  • Author(s): Takahiro Horie, Satoshi Koyama, Takeshi Kimura, Koh Ono
  • Organizer: 2019 XXIII ISHR WORLD CONGRESS
  • Int'l Joint Research
• [Presentation] Identification of Differential Roles of Microrna-33a and -33b During Atherosclerosis Progression with Genetically Modified Mice. (2019)
  • Author(s): Takahiro Horie, Satoshi Koyama, Yui Miyasaka, Takeshi Kimura, Koh Ono
  • Organizer: Basic Cardiovascular Sciences Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Identification of Differential Roles of Microrna-33a and -33b During Atherosclerosis Progression with Genetically Modified Mice (2019)
  • Author(s): Takahiro Horie, Satoshi Koyama, Yui Miyasaka, Takeshi Kimura, Koh Ono
  • Organizer: ESC Congress 2019
  • Int'l Joint Research
• [Presentation] SREBF1/MicroRNA-33b axis exhibits potent effect on unstable atherosclerotic plaque formation in vivo (2018)
  • Author(s): Takahiro Horie、Tomohiro Nishino、Tetsushi Nakao、Fumiko Nakazeki、Yuya Ide、Satoshi Koyama、Masahiro Kimura、Koji Hasegawa、Takeshi Kimura、Koh Ono
  • Organizer: Asian Pacific Society of Cardiology (APSC) Congress 2018
  • Int'l Joint Research
• [Presentation] Loss of periostin ameliorates adipose tissue inflammation and fibrosis in vivo (2018)
  • Author(s): Takahiro Horie, Fumiko Nakazeki, Masataka Nishiga, Takahiro Horie, Hitoo Nishi, Yasuhiro Nakashima, Osamu Baba, Yasuhide Kuwabara, Tomohiro Nishino, Tetsushi Nakao, Yuya Ide, Satoshi Koyama, Masahiro Kimura, Shuhei Tsuji, Naoya Sowa, Takeshi Kimura, and Koh Ono
  • Organizer: 第50回日本動脈硬化学会学術集会
  • Invited
• [Presentation] Loss of periostin ameliorates adipose tissue inflammation and fibrosis in vivo (2018)
  • Author(s): Takahiro Horie、Fumiko Nakazeki、Takeshi Kimura、Koh Ono
  • Organizer: The 2nd JCS Council Forum on Basic CaridoVascular Research
• [Presentation] SREBF1/MicroRNA-33b axis exhibits potent effect on unstable atherosclerotic plaque formation in vivo (2018)
  • Author(s): Takahiro Horie、Tomohito Nishino、Takeshi Kimura、Koh Ono
  • Organizer: The 2nd JCS Council Forum on Basic CaridoVascular Research
• [Presentation] MicroRNA in Atherosclerosis (JCS-KSC Joint Symposium (Basic Research) (2017)
  • Author(s): Takahiro Horie
  • Organizer: The 61st Annual Scientific Meeting of The Korean Society of Cardiology
  • Int'l Joint Research / Invited
• [Presentation] 動脈硬化性疾患に対する核酸医薬の可能性（シンポジウム 13 ： 脂質異常症治療薬の新展開） (2017)
  • Author(s): 堀江貴裕、木村剛、尾野亘
  • Organizer: 第65回日本心臓病学会学術集会
  • Invited
• [Presentation] Serum HDL Cholesterol decreases in microRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1). (2017)
  • Author(s): Takahiro Horie
  • Organizer: THE 43rd NAITO CONFERENCE Noncoding RNA :Biology, Chemistry, & Diseases
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice. (2017)
  • Author(s): Nishino T, Horie T, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Kimura T, Ono K
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Remarks]
  • 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 分子循環器グループ
  • 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/
• [Patent(Industrial Property Rights)] NASHの予防及び/又は治療剤 (2021)
  • Inventor(s): 尾野亘, 堀江貴裕, 西野共達, 宮川紗和, 小比賀聡, 笠原勇矢
  • Industrial Property Rights Holder: 国立大学法人京都大学 国立大学法人大阪大学 国立研究開発法人医薬基盤・健康・栄養研究所
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-097796
  • Filing Date: 2021
  • Overseas
• [Patent(Industrial Property Rights)] microRNA（miR）-33aおよびmiR-33bを個別に制御できる合成核酸医薬の開発と大動脈瘤に対する効果 (2019)
  • Inventor(s): 尾野 亘、堀江貴裕、西野共達、山崎智弘
  • Industrial Property Rights Holder: 尾野 亘、堀江貴裕、西野共達、山崎智弘
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 心筋細胞の保護用の医薬組成物 (2019)
  • Inventor(s): 垣塚彰、尾野 亘、堀江貴裕、井手裕也、斉藤成達、木村剛
  • Industrial Property Rights Holder: 垣塚彰、尾野 亘、堀江貴裕、井手裕也、斉藤成達、木村剛
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] miR-33b ノックインマウスによる非アルコール性脂肪肝炎モデル (2017)
  • Inventor(s): 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Holder: 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-059580
  • Filing Date: 2017