Elucidation of irreversible switch mechanism in hepatic stellate cell activation

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07968
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Osaka Metropolitan University (2022-2023); Osaka City University (2021)
• Principal Investigator: Matsubara Misako 大阪公立大学, 大学院獣医学研究科, 准教授 (00635120)
• Co-Investigator(Kenkyū-buntansha): 松原 勤 大阪公立大学, 大学院医学研究科, 准教授 (20628698)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 活性化肝星細胞 / サイトグロビン / 一酸化窒素 / 酸化ストレス / 肝細胞 / 線維化

Outline of Final Research Achievements

It has been reported that cytoglobin (CYGB)-deficient mice are more susceptible to spontaneous carcinogenesis than wild-type mice. The applicant has conducted research based on the hypothesis that there exists an activation switch mechanism in hepatic stellate cells (HSCs) that causes persistent and irreversible activation of HSCs, leading to the intractability of liver cirrhosis and liver cancer. In this study, using CYGB-deficient mice, we demonstrated that excessive nitric oxide (NO) released from activated HSCs inhibits mitochondrial activity in hepatocytes and causes the accumulation of reactive oxygen species. This indicates that the NO dioxygenase activity of CYGB in HSCs is essential for maintaining hepatocyte function.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

肝硬変は我が国の肝硬変患者は、B 型やC 型の肝炎ウイルス感染、生活習慣に伴う非アルコール性脂肪性肝疾患(non-alcoholic fatty liver disease, NAFLD)などを原因とし40 万人に達する。そのため、活性化肝星細胞（HSC）を標的とした新規治療法の開発が急務である。本研究は、活性化HSCにおける持続的なHSC活性化の仕組みと肝線維化進展への関与および隣接する肝細胞への影響を調べることを目的とする。今回の研究で得られる成果は肝臓だけでなく他臓器の組織修復機構の維持や破綻・線維化反応の解明やその治療法開発につながる。