Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation ~Impact of high plasma XOR on vascular injury in NAFLD~

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K09023
• 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: Osaka University
• Principal Investigator: NISHIZAWA Hitoshi 大阪大学, 医学系研究科, 講師 (20379259)
• Co-Investigator(Kenkyū-buntansha): 前田 法一 大阪大学, 医学系研究科, 寄附講座准教授 (30506308) ; 藤島 裕也 大阪大学, 医学系研究科, 助教 (10779789)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: XOR / 脂肪肝、NAFLD/NASH / 動脈硬化症 / 内臓脂肪蓄積 / プリン代謝

Outline of Final Research Achievements

Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and uric acid. Plasma XOR activity has recently been measured in human subjects. In this study, a close relationship was observed between plasma XOR activity and liver transaminases in patients with type 2 diabetes, cross-sectionally, and also across hospitalized treatment. Furthermore, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in body mass index (BMI). In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. In NASH mice, we observed increased vascular neointimal formation consisted of dedifferentiated vascular smooth muscle cells, which was significantly attenuated by a selective XOR inhibitor.
Collectively, these results suggest that increased plasma XOR activity in NAFLD/NASH is involved in the pathogenesis of vascular injury.

Free Research Field

内分泌・代謝内科学

Academic Significance and Societal Importance of the Research Achievements

本研究より、脂肪肝を有する人では血中XOR活性が高く、動脈硬化性疾患に至る可能性があることが示唆される。これまで脂肪肝は動脈硬化性疾患のハイリスク病態であることが報告されてきたが、本研究の成果により、血中XORおよび高XOR血症がそれらを結ぶ鍵分子であり治療標的であることが示唆された。