Basic research of the developmental mechanism and the therapeutic application of NASH by HNF4a and PPARa

• Project/Area Number: 16K08728
• 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): 阪口 政清 岡山大学, 医歯薬学総合研究科, 教授 (70379840) ; 柿崎 暁 群馬大学, 大学院医学系研究科, 講師 (80344935)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); 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); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 非アルコール性脂肪性肝炎 / NASH / 脂肪酸 / 脂肪肝 / 核内受容体 / マウスモデル / HNF4α / 応用動物 / 遺伝子

Outline of Final Research Achievements

We aimed to investigate the mechanism of PPARα activation in the development of NASH in HNF4α-null mice (KO mice). Expression of FATP1 was increased in KO mice, and the transactivation of FATP1 was strongly induced by PPARα. Furthermore, Decreased expression of miRNAs was identified in KO mice, and the gene involved in hepatic fibrosis was also identified as the target gene of the miRNAs. In addition, hepatic fatty acid composition was altered in KO mice with altered expression of fatty acid elongases and desaturases. These results suggests that PPARα activation by qualitative change of fatty acids might induce the development of NASH in KO mice.

Academic Significance and Societal Importance of the Research Achievements

PPARα活性化はNASHを抑制すると考えられており、PPARαのアゴニストがNASHの治療薬の候補になると考えられている。本研究から、反対にPPARαの活性化がNASH発症に重要であることが分かったため、一部のNASHの治療にはPPARα阻害剤が有効であることが推測される。NASHの原因は不明な点が多く、確立された治療法もないため、より多種類の治療薬の開発が切望されていることから、本研究は従来と異なる機構による新規のNASH治療薬や診断法の開発に有意義である。

Research Products

• [Journal Article] Hepatocyte nuclear factor 4α regulates megalin expression in proximal tubular cells. (2019)
  • Author(s): Sasaki S, Hara A, Sakaguchi M, Nangaku M, Inoue Y.
  • Journal Title: Biochem Biophys Rep Volume: 17 Pages: 87-92
  • DOI: 10.1016/j.bbrep.2018.11.010
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular S100A11 plays a critical role in spread of the fibroblast population in pancreatic cancers (2019)
  • Author(s): Takamatsu H, Yamamoto K, Tomonobu N, Murata H, Inoue Y, Yamauchi A, Sumardika W, Youyi C, Kinoshita R, Yamamura M, Fujiwara H, Mitsui Y, Araki K, Futami J, Saito K, Iioka H, Ruma MW, Putranto EW, Nishibori M, Kondo E, Yamamoto Y, Toyooka S, Sakaguchi M
  • Journal Title: Oncol Res Volume: - Issue: 6 Pages: 713-727
  • DOI: 10.3727/096504018x15433161908259
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. (2018)
  • Author(s): Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
  • Journal Title: Int J Cancer. Volume: 印刷中 Issue: 2 Pages: 569-575
  • DOI: 10.1002/ijc.31982
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. (2018)
  • Author(s): Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M
  • Journal Title: Int J Cancer. Volume: - Issue: 12 Pages: 3138-3145
  • DOI: 10.1002/ijc.31945
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Induction of Hepatic Metabolic Functions by a Novel Variant of Hepatocyte Nuclear Factor 4γ. (2018)
  • Author(s): Sasaki S, Urabe M, Maeda T, Suzuki J, Irie R, Suzuki M, Tomaru Y, Sakaguchi M, Gonzalez FJ, Inoue Y
  • Journal Title: Mol Cell Biol. Volume: 38 Issue: 24
  • DOI: 10.1128/mcb.00213-18
  • Peer Reviewed
• [Journal Article] Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. (2018)
  • Author(s): Ruma IMW, Kinoshita R, Tomonobu N, Inoue Y, Kondo E, Yamauchi A, Sato H, Sumardika IW, Chen Y, Yamamoto KI, Murata H, Toyooka S, Nishibori M, Sakaguchi M
  • Journal Title: Cancers (Basel) Volume: 10 Issue: 7 Pages: 239-239
  • DOI: 10.3390/cancers10070239
  • Peer Reviewed / Open Access
• [Journal Article] Selective incorporation of foreign functionality into fibrin gels through a chemically modified DNA aptamer (2017)
  • Author(s): Fujita H, Inoue Y, Kuwahara M.
  • Journal Title: Bioorg Med Chem Lett Volume: 28 Issue: 1 Pages: 35-39
  • DOI: 10.1016/j.bmcl.2017.11.022
  • Peer Reviewed
• [Journal Article] ｂ-1,3-galactosyl-O-glycosyl-glycoprotein ｂ-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. (2017)
  • Author(s): Sumardika I Wayan、Youyi Chen、Kondo Eisaku、Inoue Yusuke、Ruma I Made Winarsa、Murata Hitoshi、Kinoshita Rie、Yamamoto Ken-Ichi、Tomida Shuta、Shien Kazuhiko、Satoh Hiroki、Yamauchi Akira、Futami Junichiro、Putranto Endy Widya、Hibino Toshihiko、Toyooka Shinichi、Nishibori Masahiro、Sakaguchi Masakiyo
  • Journal Title: Oncology Reserch Volume: in press Issue: 3 Pages: 431-444
  • DOI: 10.3727/096504017x15031557924123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An HNF4α-microRNA-194/192 signaling axis maintains hepatic cell function. (2017)
  • Author(s): Morimoto A, Kannari M, Tsuchida Y, Sasaki S, Saito C, Matsuta T, Maeda T, Akiyama M, Nakamura T, Sakaguchi M, Nameki N, Gonzalez FJ, and Inoue Y.
  • Journal Title: J. Biol. Chem. Volume: 292 Issue: 25 Pages: 10574-10585
  • DOI: 10.1074/jbc.m117.785592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of tumor suppressor REIC/Dkk-3 by a newly improved adenovirus vector with insertion of an hTERT promoter at the 3’-side of the transgene. (2017)
  • Author(s): Putranto EW, Kinoshita R, Watanabe M, Sadahira T, Murata H, Yamamoto KI, Futami J, Kataoka K, Inoue Y, Ruma IM, Sumardika IW, Youyi C, Kubo M, Sakaguchi Y, Saito K, Nasu Y, Kumon H, Huh NH, and Sakaguchi M.
  • Journal Title: Oncol. Lett. Volume: 14 Issue: 1 Pages: 1041-1048
  • DOI: 10.3892/ol.2017.6201
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel partial agonist of GPBA reduces blood glucose level in a murine glucose tolerance test. (2017)
  • Author(s): Enomoto R, Kurosawa A, Nikaido Y, Mashiko M, Saheki T, Nakajima N, Kuroiwa S, Otobe M, Ohsaki M, Tooyama K, Inoue Y, Kuwabara N, Kikuchi O, Kitamura T, Kojima I, Nakagawa Y, Saito T, Osada H, Futahashi M, Sezutsu H, and Takeda S.
  • Journal Title: Eur. J. Pharmacol. Volume: 814 Pages: 130-137
  • DOI: 10.1016/j.ejphar.2017.08.017
  • Peer Reviewed
• [Journal Article] Identification of an S100A8 receptor neuroplastin-β and its heterodimer formation with EMMPRIN. (2016)
  • Author(s): Sakaguchi M, Yamamoto M, Miyai M, Maeda T, Hiruma J, Murata H, Kinoshita R, Ruma IM, Putranto EW, Inoue Y, Morizane S, Huh NH, Tsuboi R, Hibino T.
  • Journal Title: J Invest Dermatol. Volume: 136 Issue: 11 Pages: 2240-2250
  • DOI: 10.1016/j.jid.2016.06.617
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. (2016)
  • Author(s): Saho S, Satoh H, Kondo E, Inoue Y, Yamauchi A, Murata H, Kinoshita R, Yamamoto KI, Futami J, Putranto EW, Ruma IM, Sumardika IW, Youyi C, Suzawa K, Yamamoto H, Soh J, Tomida S, Sakaguchi Y, Saito K, Iioka H, Huh NH, Toyooka S, Sakaguchi M.
  • Journal Title: Cancer Microenviron. Volume: 9 Issue: 2-3 Pages: 93-105
  • DOI: 10.1007/s12307-016-0185-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding. (2016)
  • Author(s): Ruma IM, Putranto EW, Kondo E, Murata H, Watanabe M, Huang P, Kinoshita R, Futami J, Inoue Y, Yamauchi A, Sumardika IW, Youyi C, Yamamoto K, Nasu Y, Nishibori M, Hibino T, Sakaguchi M.
  • Journal Title: Clin Exp Metastasis Volume: 33 Issue: 6 Pages: 609-627
  • DOI: 10.1007/s10585-016-9801-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 新規HNF4γバリアントによる肝機能の誘導 (2018)
  • Author(s): 佐々木翔太, 浦部瑞穂, 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41回日本分子生物学会
• [Presentation] PPARαカスケードの活性化による新規NASH発症機構の解明 (2018)
  • Author(s): 笠野一郎, 瀧澤将行, 齊藤千夏, Frank J. Gonzalez,井上裕介
  • Organizer: 第41回日本分子生物学会
• [Presentation] 肝臓HNF4αの標的タンパク質の同定 (2018)
  • Author(s): 生井美帆, 井上 裕介
  • Organizer: 第41回日本分子生物学会
• [Presentation] 肝臓特異的HNF4α欠損マウスで発現上昇する転写因子の機能解析 (2018)
  • Author(s): 安藤翔太朗, 井上裕介
  • Organizer: 第41回日本分子生物学会
• [Presentation] 核内受容体HNF4γによる肝がん細胞の再分化誘導 (2017)
  • Author(s): 浦部瑞穂、佐々木翔太、前田つかさ、鈴木淳子、入江亮太、阪口政清、Gonzalez J. Frank、井上裕介
  • Organizer: 第40回日本分子生物学会
• [Presentation] Application of hepatocyte nuclear factor 4γ for establishment of differentiated hepatocytes (2017)
  • Author(s): S. Sasaki, M. Urabe, T. Maeda, J. Suzuki, R. Irie, M. Sakaguchi, F.J. Gonzalez, and Y. Inoue
  • Organizer: 4th International Conference on Pharmaceutical and Biomedical Engineering
  • Int'l Joint Research
• [Presentation] Induction of hepatocyte-specific gene expression by a novel nuclear receptor (2017)
  • Author(s): S. Sasaki, M. Urabe, T. Maeda, J. Suzuki, R. Irie, S. Kakizaki, F.J. Gonzalez, and Y. Inoue
  • Organizer: 4th International Symposium of Gunma University Medical Innovation and Advanced Micro-Device Engineering
  • Int'l Joint Research
• [Presentation] 肝臓におけるmiRNAを介した新規HNF4αネットワークの解明 (2017)
  • Author(s): 秋山萌、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、Frank Gonzalez、井上 裕介
  • Organizer: 第40回日本分子生物学会
• [Presentation] 肝臓特異的HNF4α欠損マウスの血糖値低下機構の解析 (2016)
  • Author(s): 吉田稜、松田強志、神成真名、Frank J. Gonzalez、井上裕介
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] HNF4αによる肺がん形成, 進行への影響 (2016)
  • Author(s): 濱田真輝、井上裕介
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] PPARαカスケードの活性化による脂肪肝の発症 (2016)
  • Author(s): 瀧澤将行、有賀長透、齊藤千夏、行木信一、Frank J. Gonzalez、井上 裕介1
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Positive regulation of Hepatic miRNA by HNF4α (2016)
  • Author(s): Akiyama M, Morimoto A, Kannari M, Tsuchida Y, Matsuta T, Saito C, Sasaki S, Kakizaki S, Gonzalez FJ, Inoue Y.
  • Organizer: 3rd International Symposium of GUMI&AMDE2016
  • Place of Presentation: 桐生市民会館
  • Int'l Joint Research