Nuclear receptor PXR-mediated hepatocyte proliferation: understanding of its mechanism and human relevance
| Project/Area Number |
17K08418
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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 |
Medical pharmacy
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| Research Institution | University of Shizuoka |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
佐々木 崇光 静岡県立大学, 薬学部, 客員共同研究員 (20382674)
保坂 卓臣 静岡県立大学, 薬学部, 助教 (30611579)
志津 怜太 静岡県立大学, 薬学部, 助教 (50803912)
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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 |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 肝毒性 / 肝細胞増殖 / 化学発がん / 肝がん / 核内受容体 / 医薬品副作用 / 抗炎症 / 分子間相互作用 / PXR / CAR / 転写調節 / 肝臓 / 細胞増殖 / 化学物質 / 肝 / 肝細胞 / 肝再生 / 種差 |
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| Outline of Final Research Achievements |
In this study, we investigated the influences of PXR activation on the chemical-induced hepatocarcinogenesis and the association of PXR with inflammatory signals by using in vivo and in vitro experiments. Mammalian two-hybrid assays showed that PXR did not interact with YAP, a key transcriptional co-factor of hepatocyte proliferation. In a mouse hepatocyte model, the knock-down of YAP did not affect PXR-mediated enhancement of mouse hepatocyte proliferation. In a mouse carcinogenesis model with diethylnitrosamine as an initiator, the CAR activator phenobarbital induced liver tumors (adenoma and/or carcinoma) but the murine PXR activator PCN did not. Interestingly, cotreatment with PCN reduced the size and multiplicity of the phenobarbital-induced liver tumors. Using in vitro reporter gene assays and in vivo liver injury model mice, PXR activation was suggested to suppress the functions of NF-κB and AP-1, which are key inflammation-related transcription factors.
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| Academic Significance and Societal Importance of the Research Achievements |
核内受容体PXRは人々が日常的に摂取する医薬品や食品成分など多種多様な化学物質により活性化される。我々のこれまでの研究成果から、PXRの活性化は、肝障害からの回復を促進する一方で化学物質による肝発がんの感受性を増強する可能性が考えられた。そこで本研究ではこれらの可能性を検討した。その結果、既知の肝化学発がんモデルにおいて、PXRの活性化自体は肝がんを惹起せず、むしろ肝がんの悪性化を抑制する可能性が示された。また、PXRは炎症関連転写因子の機能を抑制することが示唆された。今後、分子機序やヒト外挿性を明らかにする必要はあるが、本研究成果より、PXR活性化物質は抗腫瘍効果を有する可能性が示された。
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Report
(4 results)
Research Products
(26 results)
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[Journal Article] Functional interaction between PXR and YAP in xenobiotic-dependent liver hypertrophy and drug metabolism.2019
Author(s)
Abe, T., Shizu, R., Sasaki, T., Shimizu, Y., Hosaka, T., Kodama, S., Matsuzawa, A., Yoshinari, K.
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Journal Title
J. Pharmacol. Exp. Ther.
Volume: 371
Issue: 3
Pages: 590-601
DOI
Related Report
Peer Reviewed
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