The role of cathepsin Z for liver failure-type progression in primary biliary cholangitis

• Project/Area Number: 17K09449
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Department of Clinical Research, National Hospital Organization Nagasaki Medical Center
• Principal Investigator: AIBA YOSHIHIRO 独立行政法人国立病院機構(長崎医療センター臨床研究センター), 臨床研究センター, 研究員 (70450955)
• Co-Investigator(Kenkyū-buntansha): 伊東 正博 独立行政法人国立病院機構(長崎医療センター臨床研究センター), 臨床検査科, 病理医 (30184691) ; 中村 稔 独立行政法人国立病院機構(長崎医療センター臨床研究センター), 臨床研究センター, 客員研究員 (40217906) ; 高槻 光寿 長崎大学, 医歯薬学総合研究科(医学系), 客員研究員 (80380939)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 原発性胆汁性胆管炎 / ゲノムワイド関連解析 / カテプシン / 肝臓学

Outline of Final Research Achievements

Increased cathepsin Z (CSTZ) in serum and the liver and its altered localization in hepatocyte were characteristic features of end-stage of primary biliary cholangitis and other cholestatic liver diseases. Increased expression and altered localization of cathepsin B (CTSB) in serum and the liver were also observed in end-stage of these cholestatic liver diseases, CTSB was a surrogate marker for severe progression with cholestasis in PBC. Although CTSZ was not involved in bile acid-induced cell death, increased CTSZ affected signal molecules, intermediated filaments, and 3'-phosphoadenosine 5'-phosphosulfate metabolic process molecules in hepatocyte.

Academic Significance and Societal Importance of the Research Achievements

治療薬への反応が乏しく最終的に肝不全に至るPBC肝不全進行に対する救命手段は肝移植しかなく、その進行メカニズムの解明や新規治療薬の開発は重要な課題である。我々は、ゲノムワイド関連解析によりPBCの肝不全型進行に関連する遺伝子として同定したCTSZに加えてCTSBが、PBC肝不全進行と他の胆汁鬱滞性肝疾患の重症化に関与している可能性を明らかにした。これらの研究成果は、PBC肝不全進行だけでなく広く胆汁鬱滞性肝疾患の重症化メカニズムの解明や新規治療薬の開発に繋がる可能性を有する。

Research Products

• [Journal Article] Integrated GWAS and mRNA microarray analysis identified IFNG and CD40L as the most significant upstream regulators in primary biliary cholangitis. (2020)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, et al.
  • Journal Title: Hepatology Communications Volume: 4(5) Issue: 5 Pages: 724-738
  • DOI: 10.1002/hep4.1497
  • Peer Reviewed / Open Access
• [Journal Article] POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33 (2019)
  • Author(s): Hitomi, Y. Ueno, K. Kawai, Y. Nishida, N. , Umemura, T. et al
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 102-102
  • DOI: 10.1038/s41598-018-36490-1
  • NAID: 120007179055
  • Peer Reviewed / Open Access
• [Journal Article] NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional Variants. (2018)
  • Author(s): Hitomi Y, Nakatani K, Kojima K, Nishida N, Kawai Y, Kawashima M, Aiba Y, Nagasaki M, Nakamura M, Tokunaga K.
  • Journal Title: Cell Mol Gastroenterol Hepatol Volume: 7 Issue: 3 Pages: 515-532
  • DOI: 10.1016/j.jcmgh.2018.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Increased expression and altered localization of cathepsin Z are associated with progression to jaundice stage in primary biliary cholangitis (2018)
  • Author(s): Aiba Yoshihiro、Harada Kenichi、Ito Masahiro、Suematsu Takashi、Aishima Shinichi、Hitomi Yuki、Nishida Nao、Kawashima Minae、Takatsuki Mitsuhisa、Eguchi Susumu、Shimoda Shinji、Nakamura Hitomi、Komori Atsumasa、Abiru Seigo、Nagaoka Shinya、Migita Kiyoshi、Yatsuhashi Hiroshi、Tokunaga Katsushi、Nakamura Minoru
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 11808-11808
  • DOI: 10.1038/s41598-018-30146-w
  • Peer Reviewed / Open Access
• [Journal Article] NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population (2018)
  • Author(s): Nishida Nao、Aiba Yoshihiro、Hitomi Yuki、Nagasaki Masao、Tokunaga Katsushi、Nakamura Minoru et al.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8071-8071
  • DOI: 10.1038/s41598-018-26369-6
  • NAID: 120006551764
  • Peer Reviewed / Open Access
• [Presentation] 発性胆汁性胆管炎に関与する遺伝子の共発現ネットワーク解析. (2020)
  • Author(s): 相葉佳洋、植野和子、人見祐基、小森敦正、橋元悟、戸次鎮宗、阿比留正剛、長岡進矢、黒木保、八橋弘、中村稔
  • Organizer: 第56回日本肝臓学会総会.
• [Presentation] 原発性胆汁性胆管炎の肝組織網羅的遺伝子発現データを用いた疾患感受性遺伝子ならびに疾患関連pathwayの解析. (2019)
  • Author(s): 相葉佳洋、西田奈央, 人見祐基, 小森敦正, 八橋 弘, 中村 稔.
  • Organizer: 第55回日本肝臓学会総会.
• [Presentation] 原発性胆汁性胆管炎（PBC）感受性遺伝子領域に起因する発症機序の解明におけるゲノム編集技術の応用. (2019)
  • Author(s): 人見祐基, 河合洋介, 植野和子, 西田奈央, 川嶋実苗, 相葉佳洋, Olivier Gervais, Seik-Soon Khor, 築地 信, 長崎正朗, 中村 稔, 徳永勝士.
  • Organizer: 日本人類遺伝学会第64回大会.
• [Presentation] Role of PRKCB in the development of primary biliary cholangitis (2019)
  • Author(s): Aiba Y, Hitomi Y, Ueno K, Nakamura M.
  • Organizer: The 48th Annual Meeting of the Japanese Society of Immunology
• [Presentation] The role of PRKCB in the development of primary biliary cholangitis (2019)
  • Author(s): Aiba Y, Ueno K, Hitomi Y, Kawashima M, Nishida N, Kawai Y, Komori A, Yatsuhashi H, Nagasaki M, Tokunaga K, Nakamura M and PBC-GWAS consortium in Japan
  • Organizer: AASLD THE LIVER MEETING 2019.
  • Int'l Joint Research
• [Presentation] Integrated analysis of GWAS and mRNA microarray identified IFNG and CD40L as the central upstream-regulators in primary biliary cholangitis (2019)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, Shimoda S, O Gervais, Kawai Y, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, Nakamura M and PBC-GWAS Consortium in Japan.
  • Organizer: The International Liver Congress 2019 (ILC2019).
  • Int'l Joint Research
• [Presentation] Integrated analysis of GWAS and mRNA expression array identified IFNG and CD40L as the most significant upstream-regulators in primary biliary cholangitis. (2019)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, Shimoda S, O Gervais, Kawai Y, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, Nakamura M.
  • Organizer: The 69th Annual Meeting of The American Society of Human Genetics.
  • Int'l Joint Research
• [Presentation] Integrated analysis of GWAS and mRNA expression array identified IFNG and CD40L as the most significant upstream-regulators in primary biliary cholangitis. (2019)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, Shimoda S, O Gervais, Kawai Y, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, Nakamura M.
  • Organizer: The 69th Annual Meeting of The American Society of Human Genetics (ASHG 2019).
  • Int'l Joint Research
• [Presentation] Pathway-Analysis Using Datasets of GWAS and mRNA Expression Array Identified IFNG as the Most Significant Upstream-Regulator in Primary Biliary Cholangitis. (2019)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, Shimoda S, Tanaka A, Olivier Gervais, Kawai Y, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, Nakamura M, PBC-GWAS consortium in Japan.
  • Organizer: APASL STC Tokyo 2019.
  • Int'l Joint Research
• [Presentation] POGLUT1, The Effector Gene Driven by rs2293370 in Primary Biliary Cholangitis (PBC) Susceptibility Locus Chromosome 3q13.33 in The Japanese Population. (2019)
  • Author(s): Hitomi Y, Ueno K, Kawai Y, Nishida N, Kojima K, Kawashima M, Aiba Y, Shimoda S, Tanaka A, Nagasaki M, Tokunaga K, Nakamura M, PBC-GWAS Consortium in Japan.
  • Organizer: APASL STC Tokyo 2019.
  • Int'l Joint Research
• [Presentation] Integrated analysis of GWAS and mRNA microarray revealed IFN-g as the most significant signature in the disease-pathways of primary biliary cholangitis in the Japanese population (2018)
  • Author(s): Yoshihiro Aiba, Kazuko Ueno, Shinji Shimoda, Yuki Hitomi, Minae Kawashima, Nao Nishida, Yosuke Kawai, Atsumasa Komori, Hiroshi Yatsuhashi, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura, PBC-GWAS consortium in Japan et al.
  • Organizer: AASLD 2018
  • Int'l Joint Research
• [Presentation] 原発性胆汁性胆管炎の重症化にカテプシンの果たす役割の検討 (2017)
  • Author(s): 相葉佳洋, 原田憲一, 相島慎一, 伊東正博, 人見祐基, 西田奈央, 小森敦正, 八橋 弘, 中村 稔
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 日本人原発性胆汁性胆管炎における黄疸型進行関連遺伝子の同定と発現・機能解析 (2017)
  • Author(s): 相葉佳洋, 西田奈央, 人見祐基, 川嶋実苗, 徳永勝士, 中村 稔
  • Organizer: 第45回日本臨床免疫学会総会.
• [Presentation] Increased expression and altered localization of cathepsin Z is associated with progression to jaundice-stage in primary biliary cholangitis (2017)
  • Author(s): Aiba Y, Harada K, Ito M, Aishima S, Hitomi Y, Nishida N, Kawashima M, Uemoto S, Kokudo N, Takatsuki M, Eguchi S, Shimoda S, Nakamura H, Komori A, Abiru S, Nagaoka S, Yatsuhashi H, Tokunaga K, Nakamura M
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] Increased expression and altered localization of cathepsin Z is associated with progression to end-stage hepatic failure in primary biliary cholangitis (2017)
  • Author(s): Yoshihiro Aiba, Kenichi Harada, Masahiro Ito, Shinichi Aishima, Atsumasa Komori, Hiroshi Yatsuhashi, Minoru Nakamura and Headquarters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ)
  • Organizer: EASL 2017
  • Int'l Joint Research