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Understanding of mechanism underlying intracellular sorting of hepatocanalicular transporters

Research Project

Project/Area Number 23790175
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

HAYASHI Hisamitsu  東京大学, 大学院・薬学系研究科, 助教 (10451858)

Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywordsトランスポーター / 肝内胆汁うっ滞 / 細胞内ソーティング / 胆汁酸 / フェニルブ チレート / コレステロール / ABCトランスポーター / 肝細胞 / ユビキチン
Research Abstract

Bile salt export pump (BSEP) localizes on canalicular membrane of hepatocytes and mediates biliary excretion of bile salts. BSEP dysfunction attributed to its internalization from hepatocanalicular membrane and subsequent degradation causes intrahepatic cholestasis. At present, no medical therapy for this disease state has been established, because the regulatory mechanism of cell surface expression of BSEP remains to be elucidated. In this study, we explored it focusing on posttranslational machinery and demonstrated that ubiquitination, a posttranslational modification, of BSEP plays a role in its internalization via clathrin-mediated endocytosis involving the AP2 adaptor complex,an adaptor protein required for cargo selection in clathrin-mediated endocytosis.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (33 results)

All 2012 2011 Other

All Journal Article (13 results) (of which Peer Reviewed: 7 results) Presentation (15 results) (of which Invited: 2 results) Book (5 results)

  • [Journal Article] E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: structural development study and separation from farnesoid X receptor-agonistic activity.2012

    • Author(s)
      Misawa T, Hayashi H, Makishima M, Sugiyama Y, Hashimoto Y.
    • Journal Title

      Bioorg Med Chem Lett.

      Volume: 22(12) Pages: 3962-6

    • Related Report
      2012 Final Research Report
  • [Journal Article] Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2.2012

    • Author(s)
      Misawa T, Hayashi H, Sugiyama Y, Hashimoto Y.
    • Journal Title

      Bioorg Med Chem.

      Volume: 20(9) Pages: 2940-9

    • Related Report
      2012 Final Research Report 2011 Research-status Report
  • [Journal Article] AP2 adaptor complex mediates bile salt export pump internalization and modulates its hepatocanalicular expression and transport function.2012

    • Author(s)
      Hayashi H, Inamura K, Aida K, Naoi S, Horikawa R, Nagasaka H, Takatani T, Fukushima T, Hattori A, Yabuki T, Horii I, Sugiyama Y.
    • Journal Title

      Hepatology.

      Volume: 55(6) Pages: 1889-900

    • Related Report
      2012 Final Research Report
  • [Journal Article] 4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration.2012

    • Author(s)
      Hayashi H, Mizuno T, Horikawa R, Nagasaka H, Yabuki T, Takikawa H, Sugiyama Y.
    • Journal Title

      J Hepatol.

      Volume: 56(5) Pages: 1136-44

    • Related Report
      2012 Final Research Report 2011 Research-status Report
  • [Journal Article] 4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration2012

    • Author(s)
      Hayashi H
    • Journal Title

      J Hepatol

      Volume: 56 Issue: 5 Pages: 1136

    • DOI

      10.1016/j.jhep.2011.11.021

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] AP2 adaptor complex mediates bile salt export pump internalization and modulates its hepatocanalicular expression and transport function.2012

    • Author(s)
      Hayashi H
    • Journal Title

      Hepatology

      Volume: 55 Issue: 6 Pages: 1889-900

    • DOI

      10.1002/hep.25591

    • Related Report
      2012 Annual Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Sorting nexin 27 interacts with multidrug resistance-associated protein 4(MRP4) and mediates internalization of MRP42012

    • Author(s)
      Hayashi H, Naoi S, Nakagawa T, Nishikawa T, Fukuda H, Imajoh-OhmiS, Kondo A, Kubo K, Yabuki T, HattoriA, Hirouchi M, Sugiyama Y
    • Journal Title

      The Journal of Biological Chemistry

      Volume: 287 Issue: 18 Pages: 15054-65

    • DOI

      10.1074/jbc.m111.337931

    • Related Report
      2012 Annual Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 22012

    • Author(s)
      Misawa T.
    • Journal Title

      Bioorganic Medicinal Chemistry

      Volume: 20 Issue: 9 Pages: 2940-2949

    • DOI

      10.1016/j.bmc.2012.03.016

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] E297G Mutated bile salt export pump (BSEP) function enhancers derived from GW4064: Structural development study and separation from farnesoid X receptor-agonistic activity.2012

    • Author(s)
      Takashi Misawa 他4名
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 22 Issue: 12 Pages: 3962-3996

    • DOI

      10.1016/j.bmcl.2012.04.099

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ubiquitination is associated with lysosomal degradation of cell surface-resident ABCA1 through the ESCRT pathway.2011

    • Author(s)
      Mizuno T, Hayashi H, Naoi S, Sugiyama Y
    • Journal Title

      Hepatology.

      Volume: 54(2) Pages: 631-43

    • Related Report
      2012 Final Research Report
  • [Journal Article] Sugiyama Y.Calpain-mediated cleavage negatively regulates the expression level of ABCG1.2011

    • Author(s)
      Hori N, Hayashi H
    • Journal Title

      Atherosclerosis.

      Volume: 215(2) Pages: 383-91

    • Related Report
      2012 Final Research Report
  • [Journal Article] Ubiquitination is associated with lysosomal degradation of cell surface-resident ATP-binding cassette transporter A1 (ABCA1) through the endosomal sorting complex required for transport (ESCRT) pathway2011

    • Author(s)
      Tadahaya Mizuno, Hisamitsu Hayashi, Sotaro Naoi, Yuichi Sugiyama
    • Journal Title

      Hepatology

      Volume: 54 Issue: 2 Pages: 631-643

    • DOI

      10.1002/hep.24387

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Calpain-mediated cleavage negatively regulates the expression level of ABCG1.2011

    • Author(s)
      Hori N, Hayashi H, Sugiyama Y.
    • Journal Title

      Atherosclerosis.

      Volume: 215 Issue: 2 Pages: 383-91

    • DOI

      10.1016/j.atherosclerosis.2010.12.033

    • NAID

      130004640071

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] 胆汁酸トランスポーターBSEPの内在化に関わるモチーフの探索2012

    • Author(s)
      林 久允
    • Organizer
      第27年回日本薬剤学会
    • Place of Presentation
      神戸
    • Related Report
      2012 Annual Research Report
  • [Presentation] NEW DRUG DEVELOPMENT FOR LIVER DISORDERS WITH INTRAHEPATIC CHOLESTASIS2012

    • Author(s)
      林 久允
    • Organizer
      第27回日本薬物動態学会
    • Place of Presentation
      東京
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Research on the intracellular trafficking mechanisms of transporters to facilitate drug development2012

    • Author(s)
      林 久允
    • Organizer
      第27回日本薬物動態学会
    • Place of Presentation
      東京
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Role of ubiqutination in the intracellular sorting of hepatocanalicular ABC transporters2012

    • Author(s)
      Kensuke Aida
    • Organizer
      GPEN
    • Place of Presentation
      Melbourne, Australia
    • Related Report
      2012 Annual Research Report
  • [Presentation] PFIC2の原因となる変異型BSEPの機能を修正する新規小分子の発見と構造展開2012

    • Author(s)
      三澤隆史、林久允、杉山雄一、橋本祐一
    • Organizer
      日本薬学会第132年会
    • Place of Presentation
      北海道
    • Related Report
      2011 Research-status Report
  • [Presentation] AP2 adaptor complex mediates internalization of bile salt export pump and modulates its hepatocanalicular expression and transport function.2011

    • Author(s)
      Hisamitsu Hayashi, Kaori Inamura, Kensuke Aida, Sotaro Naoi, Asami Hattori, Takashi Yabuki, Yuichi Sugiyama
    • Organizer
      The Liver Meeting 2011
    • Place of Presentation
      San Francisco, US
    • Related Report
      2011 Research-status Report
  • [Presentation] Structural development study of a novel pharmacological chaperon for folding-defective bile salts export pump mutants responsible for PFIC2.2011

    • Author(s)
      Takashi Misawa, Hisamitsu Hayashi, Yuichi Sugiyama, Yuichi Hashimoto
    • Organizer
      第8回AFMC国際医薬化学シンポジウム
    • Place of Presentation
      Tokyo, Japan
    • Related Report
      2011 Research-status Report
  • [Presentation] 胆汁酸トランスポーターBSEPの細胞内ソーティングに対するユビキチン化の役割2011

    • Author(s)
      相田健佑、林久允、杉山雄一
    • Organizer
      第26年回日本薬剤学会
    • Place of Presentation
      東京
    • Related Report
      2011 Research-status Report
  • [Presentation] 胆汁酸トランスポーターBSEPの細胞内ソーティングに対するユビキチン化の役割2011

    • Author(s)
      相田健佑、林久允、杉山雄一
    • Organizer
      第19年回肝病態生理研究会
    • Place of Presentation
      東京
    • Related Report
      2011 Research-status Report
  • [Presentation] 胆汁酸トランスポーターBSEPのユビキチン化を介した細胞内ソーティング機構の解析2011

    • Author(s)
      相田健佑、林久允、稲村香央里、直井壮太朗、杉山雄一
    • Organizer
      第84回生化学会
    • Place of Presentation
      京都
    • Related Report
      2011 Research-status Report
  • [Presentation] 4-Phenylbutyrate increases the hepatocanalicular expression of MRP2/Mrp2 by modulating its ubiquitination and reduces serum total bilirubin concentration.2011

    • Author(s)
      Hisamitsu Hayashi, Tadahaya Mizuno, Reiko Horikawa, Hironori Nagasaka, Takashi Yabuki, Hajime Takikawa, Yuichi Sugiyama
    • Organizer
      第26回日本薬物動態学会
    • Place of Presentation
      広島
    • Related Report
      2011 Research-status Report
  • [Presentation] 胆汁酸トランスポーターBSEP/ABCB11のAP2との相互作用部位の探索2011

    • Author(s)
      林久允、稲村香央里、相田健佑、直井壮太朗、杉山雄一
    • Organizer
      第33回胆汁酸研究会
    • Place of Presentation
      大阪
    • Related Report
      2011 Research-status Report
  • [Presentation] 肝機能障害改善薬の開発を指向した胆汁酸トランスポーターBSEP/ABCB11の内在化制御機構の解析2011

    • Author(s)
      林久允、稲村香央里、相田健佑、直井壮太朗、杉山雄一
    • Organizer
      第33回生体膜と薬物の相互作用シンポジウム(招待講演)
    • Place of Presentation
      岡山
    • Related Report
      2011 Research-status Report
  • [Presentation] 胆汁酸トランスポーターBSEPの内在化モチーフの探索

    • Author(s)
      林 久允
    • Organizer
      第20回肝病態生理研究会
    • Place of Presentation
      金沢
    • Related Report
      2012 Annual Research Report
  • [Presentation] フォトクロミック蛍光タンパク質Dronpaを用いたLive cell imagingによる胆汁酸トランスポーターBsepの内在化評価系の構築

    • Author(s)
      相田 健佑
    • Organizer
      第20回肝病態生理研究会
    • Place of Presentation
      金沢
    • Related Report
      2012 Annual Research Report
  • [Book] 生体の科学-細胞膜タンパク質のユビキチン化-リソソーム分解経路2012

    • Author(s)
      水野 忠快
    • Total Pages
      5
    • Publisher
      医学書院
    • Related Report
      2012 Annual Research Report
  • [Book] 細胞工学-胆汁酸トランスポーターのトラフィッキング制御による創薬2012

    • Author(s)
      林 久允
    • Total Pages
      5
    • Publisher
      学研メディカル秀潤社
    • Related Report
      2012 Annual Research Report
  • [Book] 医学のあゆみ-胆汁酸トランスポーターが関連する疾患と治療2012

    • Author(s)
      林 久允
    • Total Pages
      5
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2012 Annual Research Report
  • [Book] 分子標的トランスポーター (細胞工学5月号)」, 金井好克編2012

    • Author(s)
      林久允
    • Total Pages
      6
    • Publisher
      学研メディカル秀潤社
    • Related Report
      2011 Research-status Report
  • [Book] 「トランスポートソーム 生体膜輸送機構の全体像に迫る (遺伝子医学MOOK19)」金井好克編2011

    • Author(s)
      林久允
    • Total Pages
      6
    • Publisher
      メディカルドゥ
    • Related Report
      2011 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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