Analysis of mechanism by which a Wnt/beta-catenin/CBP signaling inhibitor ameliomates NASH-induced liver fibrosis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K15584
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: YAMAJI Kenzaburo 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 研究員 (40508628)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 非アルコール性脂肪肝炎 / 肝線維化 / β-カテニン/CBPシグナル阻害剤

Outline of Final Research Achievements

NASH is a progressive fibrotic disease, which increasing the risk of developing hepatocellular carcinoma, however, there are still no efficient therapeutic strategy. In the present study, we examined efficacy of PRI-724 treatment to NASH-related liver fibrosis and characterized the mechanism of PRI-724 efficacy. By daily administering PRI-724 in NASH-induced liver fibrosis mice, normalization of hepatic architecture and decrease of collagen fibrils were observed after administration of PRI-724. Hepatic expressions of αSMA, type I and type III collagens, liver fibrosis markers, were significantly decreased. Moreover, expression of matrix metalloproteinase Mmp8 and Mmp9 in the liver were significantly increased. PRI-724 increased MMP-9 production in liver neutrophils and macrophages, therefore, MMP-9 is possibly contributing the improve of liver fibrosis. In conclusion, PRI-724, a selective Wnt/β-catenin/CBP inhibitor, shows therapeutic effect for NASH-related liver fibrosis/cirrhosis.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

NASHを含めて肝硬変や肝不全に対しては、肝移植以外にいまだ有用な根治的治療法はない。しかし、肝移植にはドナー不足や患者負担などの大きな問題がある。米国では肝移植が必要な疾患の第一位はNASHであり、大きな問題になっている。PRI-724はB型およびC型肝炎ウイルスに起因する肝硬変患者を対象として開発が進んでいる薬剤であるが、本研究ではNASHに起因する肝硬変に対してもPRI-724は治療薬となりうる可能性を示す結果が得られた。