| Project/Area Number |
18K08017
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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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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
本多 彰 東京医科大学, 医学部, 教授 (10468639)
宮崎 照雄 東京医科大学, 医学部, 准教授 (60532687)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 胆汁酸 / ウルソデオキシコール酸 / ミュリコール酸 / 肝障害 / 消化器病学 |
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| Outline of Final Research Achievements |
Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid (BA) that has hepatoprotective activity. The present study was undertaken to prove the superiority of more hydrophilic muricholic acids (MCAs) on hepatoprotection than UDCA. We used Cyp2c70/Cyp2a12 double knockout (DKO) mice with human-like hydrophobic BA composition and chronic liver injury. In DKO mice treated with UDCA, the proportion of UDCA increased to more than 60% of the total BA pool, and liver injury ameliorated somewhat. However, UDCA treatment did not completely normalize liver function tests or hepatic expressions of inflammatory cytokines. Furthermore, UDCA treatment increased hepatic concentrations of cholesterol, triglycerides, and lithocholic acid (LCA) compared with untreated DKO and wild type (WT) mice, which appears to prevent the further improvement of liver injury by UDCA. Thus, hepatoprotection by UDCA is limited, and MCAs appear to be more effective BAs for the treatment of liver injury, at least in mice.
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| Academic Significance and Societal Importance of the Research Achievements |
ウルソデオキシコール酸（UDCA）は、古くから広く肝障害の治療に使われている薬剤であるが、その効果は限定的である。UDCAの効果をさらに高めた新しい薬剤の開発を行うことが一連の研究の目的であり、本研究ではミュリコール酸（MCAs）が有力な候補物質のひとつであることを明らかにした。また、マウスを用いた胆汁酸製剤の効果判定のために、ヒトと類似の胆汁酸代謝経路を持つヒト型胆汁酸マウスを用いた検討を行ったが、胆汁酸製剤以外にも、胆汁酸代謝に影響を与える、あるいは胆汁酸によって影響を受ける様々な薬剤のスクリーニングに、本マウスを応用できる可能性がある。
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