Elucidation of the effect of mitochondrial DNA release by Bak/Bax activation on chronic liver disease
| Project/Area Number |
17K09423
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
Hikita Hayato 大阪大学, 医学系研究科, 助教 (20623044)
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| Co-Investigator(Kenkyū-buntansha) |
阪森 亮太郎 大阪大学, 医学系研究科, 助教 (10644685)
巽 智秀 大阪大学, 医学系研究科, 講師 (20397699)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 肝細胞死 / アポトーシス / 非アポトーシス型細胞死 / ミトコンドリアDNA / 肝細胞 / DNase II / 消化器内科学 / 肝臓学 / 慢性肝疾患 |
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| Outline of Final Research Achievements |
Apoptotic stimuli release mitochondrial DNA (mtDNA) from mitochondria. Under the DNase II activity decreased condition, mtDNA in the cytoplasm increased, IFN-β expression increased via TRL9, resulted in induction of non-apoptotic hepatocyte death.
In the liver of mice fed a high-fat diet, DNase II activity was reduced and non-apoptotic hepatocyte death was observed along with hepatocyte apoptosis. DNase II deficiency in hepatocytes of them increased non-apoptotic hepatocyte death and serum ALT levels, and exacerbated liver fibrosis. DNase II activity was also reduced in the livers of patients with non-alcoholic fatty liver disease.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、非アルコール性脂肪性肝疾患患者ではDNase II活性の低下を認めており、これがIFN-β発現上昇、IFN非アポトーシス型肝細胞死を誘導し、病態進展に寄与することが示唆された。
肝細胞のアポトーシス刺激がmtDNAを介して非アポトーシス型肝細胞死を誘導する経路の存在とそのヒト肝疾患における意義を明らかにした成果であり、学術的な意義は高いと考える。また、今後非アルコール性脂肪性肝疾患の進展抑制治療として、mtDNAによる非アポトーシス型細胞死誘導経路を標的とした治療薬の開発などにもつながり、臨床的にも意義の高い成果と考える。
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Report
(4 results)
Research Products
(11 results)
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[Presentation] Suppression of DNase II activity in fatty livers contributes to induction of RIP1-dependent hepatocyte necrosis through TLR9-IFNβ pathway.2017
Author(s)
Yoshinobu Saito, Hayato Hikita, Yasutoshi Nozaki, Yugo Kai, Yuki Makino, Tasuku Nakabori, Minoru Shigekawa, Takahiro Kodama, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
Organizer
AASLD 2017 The Liver meeting
Related Report
Int'l Joint Research
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