Metabolic pathways creating and maintaining ceramide diversity, and molecular mechanism of the pathology due to their impairment

2021 Fiscal Year Final Research Report

• Project/Area Number: 18H03976
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: Hokkaido University
• Principal Investigator: Kihara Akio 北海道大学, 薬学研究院, 教授 (50333620)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 脂質 / セラミド / スフィンゴ脂質 / アルファ酸化 / 代謝

Outline of Final Research Achievements

In this study, we have established an analytical system for ceramides and clarified ceramide composition in various tissues. Mutations in ALDH3A2, an aldehyde dehydrogenase that acts in the ceramide degradation pathway, cause Sjogren-Larsson syndrome (SLS). We generated SLS model mice and keratinocytes and elucidated the molecular mechanisms underlying the pathogenesis. Phytoceramides undergo fatty acid alpha-oxidation in theirs degradation pathway. Although the molecular mechanism of the fatty acid alpha-oxidation had been unknown, we have revealed it in this project. To date, the mechanism of sphingadiene-containing ceramide production had been unknown. However, we have identified the desaturase responsible for the production and clarified its enzymatic properties.

Free Research Field

脂質生化学

Academic Significance and Societal Importance of the Research Achievements

セラミドはスフィンゴ脂質の疎水性骨格をなす。スフィンゴ脂質は多機能脂質であり，セラミドの多様性はスフィンゴ脂質の多機能性を生み出している。本研究では世界最高水準のセラミド測定技術を確立し，これまで不明であった哺乳類の様々な組織中でのセラミドの多様性を明らかにした。また，それらの多様性を生み出す分子機構や病態との関連についても多くの知見を得た。本研究で確立したセラミド測定技術と知見は神経疾患や皮膚疾患をはじめとした疾患の診断と今後の治療薬開発の基盤となることが期待できる。