Role of FDXR in Iron Metabolism and Glucose Metabolism in Liver

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08524
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Chiba University
• Principal Investigator: Sakuma Ikki 千葉大学, 大学院医学研究院, 特任准教授 (70791721)
• Co-Investigator(Kenkyū-buntansha): 田中 知明 千葉大学, 大学院医学研究院, 教授 (50447299)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 鉄代謝

Outline of Final Research Achievements

Non-alcoholic steatohepatitis (NASH) is aggressive phenotype of non-alcoholic fatty liver disease (NAFLD) that is linked to a higher risk of liver-related death. It affects about 30% of NAFLD patients. However, there is currently no officially approved treatment specifically for NASH. Developing treatments based on the underlying disease mechanisms is required. The objective of this work was to investigate the involvement of FDXR, a regulator of mitochondrial iron metabolism, in the regulation of glucose metabolism in the liver and NASH development. The findings of this study indicate that FDXR knockdown in liver leads to the buildup of iron and triglycerides in the liver, heightened oxidative stress, and reduced mitochondrial oxygen consumption, resulting in insulin resistance and glucose intolerance.

Free Research Field

内分泌代謝、非アルコール性脂肪性肝疾患

Academic Significance and Societal Importance of the Research Achievements

我が国のNAFLDの有病率は約30%と増加傾向で、肝病態の進展とともに発癌リスクは上昇し、NASHでは約5/1000人・年とされている。新規NASH治療薬の開発は、肝臓がん発症の抑制という社会的、経済的なメリットが期待できる。本研究では、FDXRノックダウンは、肝臓への鉄・中性脂肪蓄積、酸化ストレス亢進、ミトコンドリア機能酸素消費の低下を引き起こし、インスリン抵抗性/耐糖能の悪化を惹起することが示唆された。本研究の成果が、新規NAFLD治療薬・糖尿病治療薬への臨床応用に展開するための基盤になることが期待される。