Cell-to-cell communication and pathogenesis triggered by hepatocyte cell death in the liver

• Project/Area Number: 18H02795
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Osaka University
• Principal Investigator: Tetsuo Takehara 大阪大学, 医学系研究科, 教授 (70335355)
• Co-Investigator(Kenkyū-buntansha): 阪森 亮太郎 大阪大学, 医学系研究科, 助教 (10644685) ; 疋田 隼人 大阪大学, 医学系研究科, 助教 (20623044)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 肝細胞 / ミトコンドリアDNA / 非アポトーシス型細胞死 / マクロファージ / 肝星細胞 / 酸化ストレス / GDF15 / Gab1 / オートファジー / アポトーシス / 肝発癌 / 細胞死 / ネクローシス

Outline of Final Research Achievements

Upon stimulation of hepatocyte apoptosis, mitochondrial DNA is released from mitochondria. In this project, we clarified that in non-alcoholic fatty liver disease, DNase II activity in hepatocytes is decreased, resulting in insufficient mitochondrial DNA degradation and induction of non-apoptotic cell death via TRL9. In addition, we found that the interaction between hepatocytes and macrophages exacerbates hepatocellular injury, that the interaction between hepatoma cells and hepatic stellate cells promotes hepatoma cell proliferation, ad that oxidative stress induced by hepatocyte apoptosis affects tumorigenesis We also clarified the mechanism by which Gab1 inhibits apoptosis in hepatocytes.

Academic Significance and Societal Importance of the Research Achievements

これまで肝細胞のアポトーシスについては、Bcl-2ファミリータンパクによるミトコンドリア経路を主とした制御が広く知られていたが、本研究成果の遂行により、生体内における肝細胞アポトーシスは他の分子や周辺細胞などを介して、複雑に制御されていることが明らかとなった。また、アポトーシスと非アポトーシス型細胞死が同じアポトーシス刺激から誘導されることも明らかとなり、今後肝疾患病態の解明や新たな治療薬開発に繋がることが期待される。

Research Products

• [Journal Article] Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis and tumorigenesis (2021)
  • Author(s): Mizutani N, Hikita H, Saito Y, Myojin Y, Sato K, Urabe M, Kurahashi T, Shiode Y, Sakane S, Murai K, Nozaki Y, Kodama T, Sakamori R, Yoshida Y, Tatsumi T, Takehara T.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: in press Issue: 6 Pages: G958-G968
  • DOI: 10.1152/ajpgi.00370.2020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration (2021)
  • Author(s): Nozaki Y, Hikita H, Tanaka S, Fukumoto K, Urabe M, Sato K, Myojin Y, Doi A, Murai K, Sakane S, Saito Y, Kodama T, Sakamori R, Tatsumi T, Takehara T.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 3363-3363
  • DOI: 10.1038/s41598-021-83082-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production (2021)
  • Author(s): Myojin Y, Hikita H, Sugiyama M, Sasaki Y, Fukumoto K, Sakane S, Makino Y, Takemura N, Yamada R, Shigekawa M, Kodama T, Sakamori R, Kobayashi S, Tatsumi T, Suemizu H, Eguchi H, Kokudo N, Mizokami M, Takehara T.
  • Journal Title: Gastroenterology . Volume: 160 Issue: 5 Pages: 1741-1754
  • DOI: 10.1053/j.gastro.2020.12.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in Mice (2020)
  • Author(s): Kurahashi Tomohide、Yoshida Yuichi、Ogura Satoshi、Egawa Mayumi、Furuta Kunimaro、Hikita Hayato、Kodama Takahiro、Sakamori Ryotaro、Kiso Shinichi、Kamada Yoshihiro、Wang I-Ching、Eguchi Hidetoshi、Morii Eiichi、Doki Yuichiro、Mori Masaki、Kalinichenko Vladimir V.、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 9 Issue: 3 Pages: 425-446
  • DOI: 10.1016/j.jcmgh.2019.10.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DNase II activated by the mitochondrial apoptotic pathway regulates RIP1-dependent non-apoptotic hepatocyte death via the TLR9/IFN-β signaling pathway (2018)
  • Author(s): Saito Yoshinobu、Hikita Hayato、Nozaki Yasutoshi、Kai Yugo、Makino Yuki、Nakabori Tasuku、Tanaka Satoshi、Yamada Ryoko、Shigekawa Minoru、Kodama Takahiro、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Cell Death & Differentiation Volume: 26 Issue: 3 Pages: 470-486
  • DOI: 10.1038/s41418-018-0131-6
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 肝癌微小環境における肝星細胞のオートファジーを介したGDF15の意義 (2020)
  • Author(s): 明神悠太、疋田隼人、竹原徹郎
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] アダプター蛋白Gab1は肝細胞アポトーシス・肝線維化・肝発癌を抑制する (2020)
  • Author(s): 水谷直揮、疋田隼人、齋藤義修、吉田雄一、小玉尚宏、阪森亮太郎、巽智秀、竹原徹郎
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] Hepatic stellate cell autophagy promotes HCC progression via GDF15 (2020)
  • Author(s): Yuta Myojin, Hayato Hikita, Masaya Sugiyama, Takahiro Kodama, Yuki Makino, Ryoko Yamada, Tasuku Nakabori, Ryotaro Sakamori, Tomohide Tatsumi, Masashi Mizokami, Tetsuo Takehara
  • Organizer: The Digital International Liver Congress of the European Association for the Study of the Liver
  • Int'l Joint Research
• [Presentation] 肝星細胞がオートファジー依存的に分泌するGDF15は肝細胞癌の進展に寄与する (2020)
  • Author(s): 明神悠太、疋田隼人、小玉尚宏、牧野祐紀、阪森亮太郎、巽智秀、溝上雅史、江口英利、竹原徹郎
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] GDF15 secreted by hepatic stellate cells accelerates HCC progression in an autophagy-dependent manner (2020)
  • Author(s): Yuta Myojin, Hayato Hikita , Masaya Sugiyama, Takahiro Kodama, Yuki Makino, Ryoko Yamada, Ryotaro Sakamori, Tomohide Tatsumi, Masashi Mizokami, Tetsuo Takehara
  • Organizer: The Liver Meeting Digital Experience
  • Int'l Joint Research
• [Presentation] HCC promotes autophagy in hepatic stellate cells, leading to HCC progression via IL-6/STAT3 signaling (2019)
  • Author(s): Yuta Myojin, Hayato Hikita ,Takahiro Kodama, Yuki Makino, Ryoko Yamada, Yoshinobu Saito, Tasuku Nakabori, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: The 54rd International Liver Congress of the European Association for the Study of the Liver
  • Int'l Joint Research
• [Presentation] 慢性肝疾患におけるマクロファージ由来TNF-αは肝細胞における非アポトーシス型の肝細胞死誘導と酸化ストレス誘導により肝発癌を促進する (2019)
  • Author(s): 齋藤 義修，疋田 隼人，工藤 慎之輔，野崎 泰俊，牧野 祐紀，中堀 輔，山田涼子，小玉 尚宏，阪森 亮太郎，巽 智秀，竹原 徹郎
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] 持続的肝細胞アポトーシスは、酸化ストレス依存的にジエチルニトロサミンによるDNA損傷を持続させ腫瘍形成を促進させる (2019)
  • Author(s): 野﨑泰俊、疋田隼人、田中聡司、水谷直揮、明神悠太、坂根貞嗣、 牧野祐紀、中堀輔、齋藤義修、小玉尚宏、阪森亮太郎、巽智秀、竹原徹郎
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] 肝癌発育進展における肝星細胞オートファジーの意義 (2019)
  • Author(s): 明神悠太、疋田隼人、竹原徹郎
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] 肝星細胞のオートファジーがNASH肝癌の発育進展に与える影響の検討 (2019)
  • Author(s): 明神悠太、疋田隼人、竹原徹郎
  • Organizer: 第26回 肝細胞研究会
• [Presentation] The autophagy in hepatic stellate cell promotes carcinogenesis and fibrosis in liver via IL6-STAT3 pathway (2019)
  • Author(s): Yuta Myojin, Hayato Hikita ,Takahiro Kodama, Yuki Makino, Ryoko Yamada, Tasuku Nakabori, Ryotaro Sakamori, Tomohide Tatsumi,Tetsuo Takehara
  • Organizer: The Liver Meeting 2019 (AASLD2019)
  • Int'l Joint Research
• [Presentation] 転写因子FoxM1を標的とした新規NASH治療法の可能性について (2019)
  • Author(s): 倉橋知英、吉田雄一、竹原徹郎
  • Organizer: 第23回日本肝臓学会大会
• [Presentation] 肝癌微小環境における肝星細胞の影響 (2019)
  • Author(s): 疋田隼人、明神悠太、牧野祐紀、小玉尚宏、竹原徹郎
  • Organizer: 第33回肝類洞壁細胞研究会学術集会
• [Presentation] 肝細胞アポトーシスに起因する慢性肝疾患におけるTNF-αの役割についての検討 (2018)
  • Author(s): 齋藤 義修，疋田 隼人，甲斐 優吾，野崎 泰俊，牧野 祐紀，中堀 輔，小玉 尚宏，阪森 亮太郎，巽 智秀，竹原 徹郎
  • Organizer: 第54回 日本肝臓学会総会
• [Presentation] 慢性肝疾患においてTNF-αが肝細胞死に及ぼす影響についての検討 (2018)
  • Author(s): 齋藤 義修，疋田 隼人，野崎 泰俊，牧野 祐紀，中堀 輔，小玉 尚宏，阪森 亮太郎，巽 智秀，竹原 徹郎
  • Organizer: 第25回 肝細胞研究会
• [Presentation] The impact of TNF-α on hepatocarcinogenesis related with continuous hepatocyte apoptosis (2018)
  • Author(s): Yoshinobu Saito, Hayato Hikita, Yuta Myojin, Yasutoshi Nozaki, Yuki Makino, Takahiro Kodama, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Persistent hepatocyte apoptosis accelerates diethylnitrosamine(DEN)-induced liver tumor formation (2018)
  • Author(s): Yasutoshi Nozaki, Hayato Hikita, Satoshi Tanaka, Yuta Myojin, Yuki Makino, Yoshinobu Saito, Takahiro Kodama, RYotaro Sakamori, Tomohide Tatsumi and Tetsuo Takehara
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Continuous hepatocyte apoptosis accelerates diethylnitrosamine-induced liver tumor development via oxidative stress (2018)
  • Author(s): Yasutoshi Nozaki, Hayato Hikita, Satoshi Tanaka, Naoki Mizutani, Sadatsugu Sakane, Yuki Makino, Tasuku Nakabori, Yoshinobu Saito, Takahiro Kodama, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: AASLD 2018 The Liver meeting
  • Int'l Joint Research
• [Presentation] The impact of TNF-α-induced non-apoptotic cell death on hepatocarcinogenesis related with continuous hepatocyte apoptosis (2018)
  • Author(s): Yoshinobu Saito, Hayato Hikita, Yasutoshi Nozaki, Yuki Makino, Tasuku Nakabori, Minoru Shigekawa, Takahiro Kodama, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: AASLD 2018 The Liver meeting
  • Int'l Joint Research