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

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07115
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• 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, 疾患制御研究分野, 主任研究員 (40508628)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 肝線維症 / NASH / Wnt/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. Our previous study showed that PRI-724 treatment to NASH-related liver fibrosis decreased hepatic expressions of αSMA, type I and type III collagens, liver fibrosis markers, Moreover, expression of matrix metalloproteinase Mmp8 and Mmp9 in the liver were significantly increased.
In the present study, we analyzed which types of macrophage play a role in MMP9 production. The number of Mmp9-positive cells in hepatic Cd68+ macrophages isolated from livers treated with PRI-724 increased 5.5-fold. Marco+Mmp9+Cd68+ Kupffer cells were only observed in the livers of mice treated with PRI-724, and Mmp9 expression in Marco+Cd68+ Kupffer cells increased 4.3-fold.
PRI-724, a selective CBP/β-catenin inhibitor, thus shows a potent therapeutic effect for NASH-related liver fibrosis.

Free Research Field

肝臓学

Academic Significance and Societal Importance of the Research Achievements

肝硬変や肝不全に対しては肝移植以外に根治的治療法はなく、肝移植にはドナー不足や患者負担など大きな問題がある。Wnt/β-カテニン/CBPシグナル阻害剤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臨床試験が進んでいる薬剤であり、その有効性が示されている。NASHの有病数は世界で約4億4千万人であり、今後はさらに増加すると推定されている。アメリカでは、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。本研究課題の結果から、PRI-724はNASHに起因する肝硬変に対しても治療薬となりうる可能性を示すことができた。