Elucidation of a novel inflammation amplification loop by ganglioside molecular species

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H04767
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: INOKUCHI Jin-ichi 東北医科薬科大学, 薬学部, 教授 (70131810)
• Research Collaborator: GO shinji ; VEILLON lucas ; KANOH hirotaka ; GO shinji ; NAGAFUKU masakazu ; SUZUKI akemi ; UEMURA satoshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: スフィンゴ糖脂質 / ガングリオシド / 生活習慣病

Outline of Final Research Achievements

The roles of gangliosides, such as GM3 and its synthesizing enzyme GM3 synthase (GM3S), in NPC1L1-dependent cholesterol uptake have not been examined previously. Here, we examined NPC1L1-dependent cholesterol uptake in a cell model as well as in wild-type and apoE-deficient mice. We showed that NPC1L1-dependent cholesterol uptake was impaired in GM3S-deficient cells and that GM3S deficiency promoted resistance to hypercholesterolemia. We also found that KKAy GM3S KO generated by KO of the GM3S gene in the yellow obese strain, KKAy, displayed significant amelioration of obese phenotype. Whereas KKAy mice were hyperphagic and developed severe obesity, KKAy GM3S KO mice had significantly lower body weight and food intake, and greater glucose and insulin tolerance.
Our findings suggest that GM3 and related gangliosides are essential for NPC1L1-mediated intestinal cholesterol absorption and play a important role leptin-melanocortin signaling.

Free Research Field

糖鎖生物学。特に、メタボリックシンドロームおよび慢性炎症におけるスフィンゴ糖脂質の機能解明。

Academic Significance and Societal Importance of the Research Achievements

脂質異常症におけるガングリオシドの役割を調べることを目的として、自然発症apoE欠損(apoE-/-)マウスのGM3合成酵素を欠損したところ、apoE-/-マウスが示す血漿コレステロール値が劇的に改善すること、GM3S欠損(GM3S-/-)マウスが食餌誘導性の高コレステロール血症に対して抵抗性を示すことを見出した。
また、KKAyマウスにおけるGM3S KOでは、KKAyマウスの過食と肥満，耐糖能異常およびインスリン抵抗性の著明な改善がみられた。これらの結果から、GM3および関連ガングリオシドは、メタボリックシンドロームの治療標的になり得ることを示唆することができた。