Elucidation of NASH hepatocarcinogenesis mechanism and therapeutic application using oxidative DNA damage repair enzyme-deficient mice

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17405
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Tanaka Shingo 札幌医科大学, 医学部, 助教 (60561024)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: NASH / NAFLD / MUTYH / モデルマウス / 鉄過剰

Outline of Final Research Achievements

The applicants established a new NASH model mouse created by loading high-calorie and high-oxidative stress on oxidative DNA injury repair enzyme (MUTYH)-deficient mice. The purpose of this study was to evaluate this mice and to develop a novel antioxidant therapy.
Increased levels of 4-HNE and 8-OHdG, which are indicators of oxidative stress, were observed in the liver tissue of mice fed a high-fat, cholesterol and iron-rich diet(HFHC+Fe). When MUTYH-null mice were fed with HFHC+Fe, 25% of the mice showed liver tumors. Comparison of gene expression revealed that Wnt/β catenin signaling, which is relatively frequent in human hepatocellular carcinoma, is involved.

Free Research Field

消化器病学，肝臓病学，NASH，酸化ストレス

Academic Significance and Societal Importance of the Research Achievements

マウスモデルとヒトの類似性を考える上で，NASHをメタボリック症候群の肝臓部分症として捉えることが重要視され，肥満やインスリン抵抗性を示さないマウスモデルの使用が減少している．例として，メチオニン・コリン欠乏食モデルは従来広く使用されてきたが，体重減少，低血糖，低インスリン血症を呈するなど，メタボリック症候群と正反対の表現型を呈する．
ヒトのファストフードに類似した食餌を与え肥満となり，かつ酸化ストレス負荷を与えることで肝発癌をきたす本マウスは，これまで報告されたマウスの様々な問題点を解決できる可能性がある．