Identification of oxidized lipid metabolites in which involves lipid oxidation dependent novel cell death using deuterium-labeled phospholipids

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14906
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kitasato University
• Principal Investigator: SAKAMOTO TARO 北里大学, 薬学部, 講師 (10383655)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 酸化脂質 / フラクソーム解析 / 重水素型リン脂質 / 細胞死 / 脂質代謝

Outline of Final Research Achievements

Glutathione peroxidase 4 (GPx4) is a unique antioxidant enzyme that directly reduces the phospholipid hydroperoxides generated in biomembranes. We have demonstrated that the disruption of GPx4 leads to phospholipid hydroperoxide dependent novel cell death. In this study, by the fluxome analysis using deuterium labelled-phospholipid, we attempted to generate the whole aspect of metabolic map for phospholipid hydroperoxides. We found the phospholipase activity was elevated in the GPx4-depleted cells as compared with that of control cells. In addition, reacylation of lysophospholipids was decreased in the GPx4-depleted cells. These data indicate that the lysophospholipids were metabolized to unknown compounds in the GPx4-depleted cells.

Free Research Field

脂質生化学

Academic Significance and Societal Importance of the Research Achievements

GPx4欠損による新規細胞死は、GPx4ノックアウトマウスの胚致死を誘導するだけでなく、心不全性突然死、雄性不妊、COPDなどにも関わることを研究代表者らは明らかにしている。本研究では、GPx4欠損時にリゾリン脂質からリン脂質への再アシル化活性が低下し、代わりに未知の物質へと代謝される可能性を見出している。今後、実際にどういった代謝物に変化するのかが明らかとなれば、上記のような疾患のバイオマーカーへ利用できる可能性が高い。