Exploring novel bioactivities of dietary components by focusing on qualitative changes in lipoproteins

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22797
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Yamanashi Yoshihide 東京大学, 医学部附属病院, 助教 (20582018)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: VLDL / LDL / S1P / スフィンゴミエリン / NPC1L1

Outline of Final Research Achievements

Comprehensive analyses of lipoprotein components in mice revealed that VLDL/LDL-associated sphingosine-1-phosphate (S1P) was increased by feeding a high-fat diet (HFD). Interestingly, this increase was abolished in mice genetically deficient NPC1L1, an intestinal cholesterol importer, and in mice treated with ezetimibe, an NPC1L1 inhibitor. Since S1P is a metabolite of sphingomyelin (SM), which is abundant in HFD, we hypothesized that NPC1L1 is involved in intestinal SM absorption. To test this possibility, we conducted a series of in vitro and in vivo experiments and revealed that SM is a physiological substrate of NPC1L1 and its intestinal absorption is regulated by an ezetimibe-sensitive and NPC1L1-dependent pathway.

Free Research Field

脂質動態学

Academic Significance and Societal Importance of the Research Achievements

コレステロール吸収輸送体であるNPC1L1がSMの消化管吸収にも関わり、血液中のVLDL/LDL-S1Pレベルを制御することが示唆された。これらの成果はスフィンゴ脂質の恒常性維持におけるNPC1L1の新たな生理的役割を明らかにした点で、また、食事依存的なVLDL/LDLの構成成分の変化にNPC1L1が関わる可能性を見出した点で、生理学的・栄養学的に重要な知見である。