Analysis of physiological functions of oxidized phospholipid-dependent cell death by SMS2

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07050
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kitasato University
• Principal Investigator: Kumagai Takeshi 北里大学, 薬学部, 講師 (30365184)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 酸化脂質 / スフィンゴミエリン合成酵素2(SMS2) / 細胞死 / フェロトーシス / 酸化ストレス

Outline of Final Research Achievements

The purpose of this study was to elucidate the suppression mechanism of oxidized lipid-dependent cell death induced by GPx4 deficiency by SMS2 and to demonstrate whether SMS2 has antioxidant function in vivo. As a result, we clarified that localization of SMS2 at the plasma membrane is important for suppression of cell death by GPx4 deficiency. In addition, we showed that the DAG acyltransferase and DAG lipase pathways were involved. Furthermore, in order to demonstrate that SMS2 suppresses cell death by oxidative phospholipid metabolism in vivo, we used liver-specific GPx4/SMS2 double-deficient mice and examined the effects of SMS2 on the oxidative stress load on the liver. As a result, it was suggested that lethality due to liver damage induced by administration of concanavalin A was significantly enhanced in GPx4/SMS2 double-deficient mice. These results demonstrate for the first time that SMS2 has the activity to metabolize oxidized lipids in vivo.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

これらの成果は、SMS2の新たな“抗酸化酵素”としての機能を初めて明らかにしたものであり、脂質代謝酵素が酸化脂質を代謝する抗酸化機能を有することを実証した点で意義は大きい。また、近年注目されている酸化脂質依存的な細胞死の機構の解明や新たな治療法の開発につながるものであり、今後SMS2が酸化脂質が関与する疾患の治療のためにターゲットとなることが期待される。