Analysis of the pathological mechanism of NASH by the nuclear receptors and establishment of the therapeutic application

• Project/Area Number: 25460490
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Gunma University
• Principal Investigator: Inoue Yusuke 群馬大学, 大学院理工学府, 准教授 (90304302)
• Co-Investigator(Kenkyū-buntansha): NAMEKI Nobukazu 群馬大学, 大学院理工学府, 准教授 (80302959) ; SAKAGUCHI Mayakiyo 岡山大学, 大学院医歯薬総合研究科, 准教授 (70379840)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: NASH / 核内受容体 / HNF4α / PPARα / PPAR

Outline of Final Research Achievements

Deletion of PPARα in liver-specific HNF4α-null mice (KO mice) improved NASH. Expression of FATP1, CD36, and CideA was increased in KO mice, but the expression of these genes were decreased in double KO mice. Also, DNA binding activity of PPARα and the amount of hepatic fatty acid was increased in KO mice. These results indicate that ligand-activated PPARα/PGC1α could transactivate the PPARα target genes and might induce NASH in KO mice.

Research Products

• [Journal Article] Hepatocyte Nuclear Factor 4α Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver (2015)
  • Author(s): Matsuo S, Ogawa M, Muckenthaler MU, Mizui Y, Sasaki S, Fujimura T, Takizawa M, Ariga N, Ozaki H, Sakaguchi M, Gonzalez FJ, Inoue Y
  • Journal Title: J Biol Chem Volume: 290 Issue: 52 Pages: 30855-30865
  • DOI: 10.1074/jbc.m115.694414
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DNAX-activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes (2014)
  • Author(s): Sakaguchi M, Murata H, Aoyama Y, Hibino T, Putranto EW, Ruma IM, Inoue Y, Sakaguchi Y, Yamamoto K, Kinoshita R, Futami J, Kataoka K, Iwatsuki K, Huh NH
  • Journal Title: J Biol Chem Volume: 289 Issue: 34 Pages: 23389-23402
  • DOI: 10.1074/jbc.m114.573071
  • NAID: 120006333870
  • Peer Reviewed / Open Access
• [Journal Article] Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells. (2014)
  • Author(s): Ruma IMW, Putranto EW, Kondo E, Watanabe R, Saito K, Inoue Y, Yamamoto K, Nakata S,Kaihata M, Murata H and Sakaguchi M.
  • Journal Title: Int J Oncol. Volume: 45(1) Issue: 1 Pages: 209-18
  • DOI: 10.3892/ijo.2014.2397
  • Peer Reviewed / Open Access
• [Journal Article] Dramatic Increase in Expression of a Transgene by Insertion of Promoters Downstream of the Cargo Gene (2014)
  • Author(s): Masakiyo Sakaguchi, Masami Watanabe, Rie Kinoshita, Haruki Kaku, Hideo Ueki, Junichiro Futami, Hitoshi Murata, Yusuke Inoue, Shun-Ai Li, Peng Huang, Endy Widya Putranto, I. Made, Winarsa Ruma, Yasutomo Nasu, Hiromi Kumon, Nam-ho Huh
  • Journal Title: Mol. Biotechnol Volume: 56 Issue: 7 Pages: 621-630
  • DOI: 10.1007/s12033-014-9738-0
  • Peer Reviewed
• [Journal Article] Regulation of the F11, Klkb1, Cyp4v3 gene cluster in livers of metabolically challenged mice. (2013)
  • Author(s): Safdar H, Cleuren AC, Cheung KL, Gonzalez FJ, Vos HL, Inoue Y, Reitsma PH, van Vlijmen BJ.
  • Journal Title: PLoS One Volume: 8 Issue: 9 Pages: e74637-e74637
  • DOI: 10.1371/journal.pone.0074637
  • Peer Reviewed
• [Journal Article] DOCK7 is a critical regulator of the RAGE-Cdc42 signaling axis that induces formation of dendritic pseudopodia in human cancer cells (2013)
  • Author(s): Yamamoto K, Murata H, Putranto EW, Kataoka K, Motoyama A, Hibino T, Inoue Y, Sakaguchi M, and Huh NH
  • Journal Title: Oncol Rep Volume: 29 Issue: 3 Pages: 1073-1079
  • DOI: 10.3892/or.2012.2191
  • Peer Reviewed
• [Presentation] Hepatic HNF4α cascade through modulation of miR-194/192 (2015)
  • Author(s): Morimoto A, Kannari M, Tsuchida Y, Matsuta T, Saito C, Sasaki S, Maeda T, Kakizaki S, Gonzalez FJ, and Inoue Y
  • Organizer: 2nd International Symposium of Gunma University Medical Innovation
  • Place of Presentation: 前橋
  • Year and Date: 2015-12-08
  • Int'l Joint Research
• [Presentation] HNF4αはmiR-194/192を介して肝細胞の脱分化を抑制する (2015)
  • Author(s): 守本葵，神成真名，土田雄一，松田強志，齊藤千夏，佐々木翔太，前田つかさ，阪口政清，行木信一，Frank J Gonzalez，井上裕介
  • Organizer: 第38回日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-02
• [Presentation] HNF4γの転写活性化能の解析と相互作用タンパク質の探索 (2015)
  • Author(s): 佐々木翔太, 前田つかさ, 浦部瑞穂, 鈴木淳子, 入江亮太, 阪口政清, Frank J. Gonzalez, 井上裕介
  • Organizer: 第38回日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-02
• [Presentation] HNF4γの機能解析 (2015)
  • Author(s): 佐々木翔太、前田つかさ、鈴木淳子、入江亮太、阪口政清、Frank J. Gonzalez、井上裕介
  • Organizer: 日本生化学会関東支部例会
  • Place of Presentation: 新潟
  • Year and Date: 2015-06-20
• [Presentation] Investigation of a novel HNF4α network through miR-194/192 (2014)
  • Author(s): A. Morimoto, M. Kannari, Y. Tsuchida, T. Matsuta, C. Saito, S. Sasaki, T. Maeda, F.J. Gonzalez, and Y. Inoue
  • Organizer: 1st International Symposium of Gunma University Medical Innovation and
6th International Conference on Advanced Micro-Device Engineering
 (GUMI&AMDE2014)
  • Place of Presentation: 桐生市市民文化会館（群馬県桐生市）
  • Year and Date: 2014-12-05
• [Presentation] 肝臓特異的HNF4α欠損マウスにおけるHNF4γの機能解析 (2014)
  • Author(s): 佐々木翔太，前田つかさ，鈴木淳子，入江亮太，阪口政清，Frank J. Gonzalez，井上裕介
  • Organizer: 第37回日本分子生物学会，
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-27
• [Presentation] miR-194/192を介した新規HNF4αネットワークの解明 (2014)
  • Author(s): 守本葵，神成真名，土田雄一，松田強志，齊藤千夏，佐々木翔太，前田つかさ，井上裕介
  • Organizer: 第37回日本分子生物学会，
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-27
• [Presentation] PPARαカスケードの活性化による脂肪肝の発症 (2014)
  • Author(s): 有賀長透，齊藤千夏，瀧澤将行，行木信一，Frank J. Gonzalez，井上裕介
  • Organizer: 第37回日本分子生物学会，
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-27
• [Presentation] Investigation of the role of hepatic HNF4γ (2014)
  • Author(s): T. Maeda, S. Sasaki, J. Suzuki, R. Irie, F.J. Gonzalez, and Y. Inoue
  • Organizer: International symposium on “homeostasis through development, life, and diseases”
  • Place of Presentation: 群馬大学（群馬県前橋市）
  • Year and Date: 2014-11-07
• [Presentation] miR-194/192を介した新規HNF4αネットワークの解明 (2014)
  • Author(s): 守本葵，神成真名，土田雄一，齊藤千夏，松田強志，前田つかさ，佐々木翔太，行木信一，井上裕介
  • Organizer: 第16回日本RNA学会
  • Place of Presentation: ウインクあいち（愛知県名古屋市）
  • Year and Date: 2014-07-24
• [Presentation] HNF4α による miR-194/192 の発現制御機構の解析と標的遺伝 子の同定 (2013)
  • Author(s): 神成真名、松田強志、齊藤千夏、土田雄一、前田つかさ、守 本葵、行木信一、井上裕介
  • Organizer: 第15回日本RNA学会
  • Place of Presentation: 愛媛県県民文化会館（松山市）
• [Presentation] ミトコンドリアにおける翻訳停滞解消因子 ICT1 および C12orf65 の機能解析 (2013)
  • Author(s): 小暮裕幸、半田佳宏、井上裕介、行木信一
  • Organizer: 第15回日本RNA学会
  • Place of Presentation: 愛媛県県民文化会館（松山市）
• [Presentation] 2型トランスフェリン受容体遺伝子の転写活性化機構の解析 (2013)
  • Author(s): 小川正之、松尾峻介、藤村岳史、水井 由美子、Gonzalez FJ、井上裕介
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] HNF4αによるmiR-194/192の発現制御機構の解析と標的遺伝子の同定 (2013)
  • Author(s): 神成真名、守本葵、土田雄一、齊藤千夏、松田強志、前田つかさ、行木信一、井上裕介
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] HNF4αによる補体遺伝子C8γの転写活性化機構の解析 (2013)
  • Author(s): 大橋真衣子、横田聡美、坂本憲昭、Gonzalez FJ、井上裕介
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] 肝臓特異的HNF4α欠損マウスの血糖値低下機構の解明 (2013)
  • Author(s): 松田強志、神成真名、Gonzalez FJ、井上裕介
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] PPAR αカスケードの活性化は肝臓特異的HNF4α欠損マウスで脂肪肝を発症する (2013)
  • Author(s): 齊藤千夏、有賀長透、Gonzalez FJ、行木信一、井上裕介
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] 肝臓特異的HNF4α欠損マウスにおけるHNF4γの機能解析 (2013)
  • Author(s): 前田つかさ、佐々木翔太、鈴木淳子、入江亮太、外丸靖浩、鈴木正則、太期健二、Gonzalez FJ、阪口政清、行木信一、井上裕介
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場（神戸市）