Role of endothelial mitochondrial dysfunction on cardiovascular diseases associated with NASH

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K10555
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 58040:Forensics medicine-related
• Research Institution: Kyoto University
• Principal Investigator: Miyao Masashi 京都大学, 医学研究科, 講師 (90711466)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 法医病理学

Outline of Final Research Achievements

Nonalcoholic steatohepatitis (NASH), liver manifestation of a metabolic syndrome, has been demonstrated to be an independent risk factor for cardiovascular disease (CVD). However, the association between mitochondrial dysfunction of endothelial cells, NASH, and CVD remains elusive. We have tested the hypothesis whether mitochondrial fission in endothelial cells could have a causative role in NASH and CVD progression. Contrary to our hypothesis, excessive mitochondrial fissions were not induced in endothelial cells. However, we found that excessive fissions were profoundly induced in hepatocytes, and the blockade of the fissions in hepatocytes could lead to amelioration of NASH progression, especially in the early NASH phase. These findings provide new insights into the potential therapeutic strategies to prevent obesity-related morbidity and mortality.

Free Research Field

法医学

Academic Significance and Societal Importance of the Research Achievements

肥満関連疾患の中で最も若年層の有病率が高く、病態理解の進んでいないNASHは全世界で増え続けており、その予防・治療法開発は持続可能な社会の発展にとって重要である。私たちはモデルマウスを用いた実験研究で、血管内皮やマクロファージ、伊東細胞のミトコンドリア障害ではなく、肝細胞内ミトコンドリアの過剰分裂がNASHの病態を進めてしまう原因となりうることを明らかにした。このように、NASHの病態に関連するものを明らかにしていくことで、肥満病態の危険性と予防可能性の啓発、新たな診断・予防法開発につなげ、1人でも多くの予防可能な死を減らすことに貢献したい。