The regulatory mechanism of non-alcoholic fatty liver disease (NAFLD) through iron metabolism and its clinical application

2023 Fiscal Year Final Research Report

• Project/Area Number: 20KK0373
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• 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)
• Project Period (FY): 2021 – 2023
• Keywords: 鉄代謝 / TCA回路

Outline of Final Research Achievements

TCA cycle flux is thought to be decreased in non-alcoholic steatohepatitis (NASH) as a result of altered mitochondrial function. This leads to the worsening of fatty liver and an increase in oxidative stress, both of which are linked to the pathological advancement of NASH. The objective of this work was to clarify the role of FDXR in NASH by employing hepatic metabolic flux studies. The study found that mice with Fdxr knockdown had decreased flux in key enzymes of the TCA cycle, including succinate dehydrogenase, isocitrate dehydrogenase, and oxoglutarate dehydrogenase. This reduction in mitochondrial TCA cycle flux may cause the pathological progression of NASH, suggesting that Fdxr knockdown may play a role in the development of NASH.

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、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。本研究の結果から、Fdxrノックダウンマウスは、TCA回路を構成するコハク酸デヒドロゲナーゼ、イソクエン酸デヒドロゲナーゼ、オキソグルタレートデヒドロゲナーゼのフラックス低下を認め、FDXRノックダウンは、ミトコンドリアTCA回路フラックスの低下を介して、NASHの病態進展に関わることが示唆された。本研究の成果が、新規NASH治療薬に展開するための基盤になることが期待される。