Role of extracellular ATP on Hepatic stellate cell activation and liver fibrosis development

• Project/Area Number: 17K15952
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Ehime University
• Principal Investigator: Yoshida Osamu 愛媛大学, 医学部附属病院, 講師 (70746809)
• Research Collaborator: Imai Yusuke
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝星細胞 / 細胞外ATP / P2X7 / PKR / 線維化 / 肝線維化 / 内科

Outline of Final Research Achievements

P2X7, extracellular ATP receptor, expression on hepatic stellate cell(HSC) was confirmed by RT-PCR and Western blotting assay. However, HSC activation by ATP was not mediated by P2X7. Although liver cirrhosis model was established on P2X7 knockout mouse, the severity of fibrosis was similar with wild type.
We have found that soluble agent from HSC promoted HCC development. Further the HCC development was regulated by protein kinase R(PKR) on HSC.

Academic Significance and Societal Importance of the Research Achievements

肝星細胞の活性化における細胞外ATP、P2X7の役割を明らかにすることはできなかった。
一方で、肝細胞癌の進展に肝星細胞が分泌する液性因子が寄与することを明らかにした。さらに肝星細胞の液性因子分泌はPKRが制御することを明らかにした。この成果は、肝硬変患者における肝細胞癌の進展機序の解明にみならず、新規治療薬の標的となる可能性を秘めている。肝星細胞におけるPKRの役割をさらに追及することで、肝の線維化に対する新しい治療法の開発も可能とする可能性を秘めている。

Research Products

• [Journal Article] Stimulated hepatic stellate cell promotes progression of hepatocellular carcinoma due to protein kinase R activation (2019)
  • Author(s): Imai Y, Yoshida O, Watanabe T, Yukimoto A, Koizumi Y, Ikeda Y, Tokumoto Y, Hirooka M, Abe M, Hiasa Y
  • Journal Title: PLos One Volume: 14 Issue: 2 Pages: e0212589-e0212589
  • DOI: 10.1371/journal.pone.0212589
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 肝星細胞におけるProtein Kinase Rが肝細胞癌の進展に及ぼす影響 (2018)
  • Author(s): 今井祐輔、吉田理、行本敦、渡辺崇夫、小泉洋平、徳本良雄、廣岡昌史、阿部雅則、日浅陽一
  • Organizer: 第32回肝類洞壁細胞研究会
• [Presentation] Validation of the Globe Score and UK-PBC Risk Score in Japanese Patients (2018)
  • Author(s): Osamu Yoshida, Masanori Abe, Kotaro Sunago, Atsushi Yukimoto, Yusuke Imai, Yoshiko Nakamura, Takao Watanabe, Yohei Koizumi, Masashi Hirooka, Teru Kumagi, Yoichi Hiasa
  • Organizer: 27th Annual Conference of the Asian Pacific Association for the Study of the Liver
  • Int'l Joint Research
• [Presentation] 肝形質細胞様樹状細胞による肝移植免疫寛容の誘導 (2017)
  • Author(s): 吉田理
  • Organizer: 肝類洞壁細胞研究会