Inhibition of liver fibrosis by cell type-specific deficiency of group IVA PLA2 as a novel therapeutic strategy for NASH

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07077
• 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: Kyoto Pharmaceutical University
• Principal Investigator: AKIBA Satoshi 京都薬科大学, 薬学部, 教授 (70231826)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 非アルコール性脂肪肝炎 / 肝線維化 / ホスホリパーゼA2 / 類洞内皮細胞 / 肝星細胞

Outline of Final Research Achievements

Non-alcoholic steatohepatitis (NASH) is characterized by hepatic fibrosis with inflammation. However, effective pharmacotherapeutic strategies for hepatic fibrosis remain to be established. Among the initiators of inflammation, we have been investigating the possible involvement of group IVA phospholipase A2 (IVA-PLA2), which catalyzes the generation of lipid proinflammatory mediators, in the progression of hepatic fibrosis. The present study explored which types of cells in the liver are involved in IVA-PLA2-mediated hepatic fibrosis using cell-specific IVA-PLA2-conditional knockout mice. The results suggest that IVA-PLA2 in endothelial cells plays a role in the hepatic stellate cell (HSC)-mediated progression of hepatic fibrosis. Furthermore, IVA-PLA2 in HSCs mediates the generation of monocyte chemotactic protein-1, which induces infiltration of monocytes/macrophages that activate HSCs. Thus, IVA-PLA2 may be a pharmacotherapeutic target for hepatic fibrosis in NASH.

Free Research Field

病態生化学

Academic Significance and Societal Importance of the Research Achievements

本研究では、肝組織の類洞内皮細胞または肝星細胞のIVA-PLA2を選択的に欠損させたマウスにおいて、高脂肪食誘発性のNASH病態における肝線維化が軽減することを見出した。このことから類洞内皮細胞のIVA-PLA2は毛細血管化および肝星細胞の活性化を介して、肝星細胞のIVA-PLA2は単球走化因子の発現を介して、それぞれ肝線維化を進展させる分子機構を解明した点で学術的意義は高い。さらに本研究成果は、類洞内皮細胞と肝星細胞のIVA-PLA2を阻害することが、副作用の発現リスクを抑えた高効果的な肝線維症の治療に繋がることを示しており、NASHの薬物療法の実現化に貢献する点で社会的意義も高いと考える。