| Project/Area Number |
18K15824
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Nara Medical University |
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Principal Investigator |
Kaya Daisuke 奈良県立医科大学, 医学部附属病院, 研究員 (70812501)
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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 |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 非アルコール性脂肪肝炎 / 肝線維化 / 糖尿病 / 胆汁酸 / liver fibrosis / TGR5 / DPP4 / diabetes mellitus / NASH / Oleanokic acid |
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| Outline of Final Research Achievements |
This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究ではOAとDPP4阻害薬(DPP4-I)を併用することにより、効果的に肝線維化抑制効果を示すことが証明できた。TGR5アゴニストの開発が進んでいる中で、本研究の結果を踏まえ、将来的にTGR5アゴニストのNASH肝硬変、肝癌予防効果が期待できる。さらにDPP4-Iは糖尿病治療薬として最も広く使用されている薬剤であり、肝硬変患者でも比較的安全に服用可能である。現在までTGR5アゴニストとDPP4-Iの相加相乗効果に関する報告はなく、臨床でも併用による効果増強が証明できれば、TGR5アゴニストの更なる有用性とともに、慢性肝疾患の多数を占めるNASH患者の予後改善につながることが期待できる。
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