Mechanism of enhanced hepatotoxicity through fatty acid metabolic imbalance in the progression of fatty liver disease

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08315
• 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: Juntendo University
• Principal Investigator: Kon Kazuyoshi 順天堂大学, 医学部, 先任准教授 (30398672)
• Co-Investigator(Kenkyū-buntansha): 池嶋 健一 順天堂大学, 医学部, 教授 (20317382) ; 李 賢哲 順天堂大学, 医学部, 助教 (30758321) ; 千葉 麻子 順天堂大学, 医学部, 准教授 (40532726)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 脂肪毒性 / 脂肪酸不飽和化酵素 / 非アルコール性脂肪肝炎 / 肝がん / 肝線維化 / 抗酸化物質

Outline of Final Research Achievements

To investigate the induction mechanism and effects of lipotoxicity in the progression of fatty liver disease, we conducted studies using animal models mimicking some processes of fatty liver disease. Mice with imbalance in lipid metabolism by reduction of fatty acid desaturase 2 showed exacerbation of steatohepatitis and hepatic fibrosis due to a high-fat/high-cholesterol diet. Hepatocyte-specific PTEN knockout mice, a model of steatohepatitis-associated liver carcinogenesis, exhibited a decrease in antioxidants and an increase in inflammatory cytokines during the process from steatohepatitis to hepatocellular carcinogenesis, all which were suppressed by glycine administration. In addition, anti-tumor immunity was also enhanced and hepatocarcinogenesis was significantly reduced by glycine. It was suggested that lipid metabolism imbalance contributes to exacerbation of steatohepatitis, and that lipotoxicity impairs antitumor immunity and leads to hepatocarcinogenesis.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、脂肪酸代謝の変調による脂肪毒性の増加が脂肪肝炎を増悪させ、肝線維化を亢進させることが明らかになり、加齢に伴う脂肪肝炎増悪のメカニズムの一端が明確になった。脂肪酸代謝酵素の評価が脂肪肝炎増悪リスクのスクリーニングに有用である可能性、脂肪酸代謝酵素を標的とした新規治療法の可能性が示され、現在の脂肪肝炎のもつ諸問題の解決に重要な知見を得ることができた。さらに抗腫瘍免疫の制御に脂肪毒性の関与が示唆されたことは重要であり、脂肪肝炎の重大な予後規定因子である肝発がんの早期発見および治療法の確立に寄与しうる学術的意義の大きな結果が得られた。