| 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 |
|
|---|
| Research Collaborator |
GO shinji
VEILLON lucas
KANOH hirotaka
NAGAFUKU masakazu
SUZUKI akemi
UEMURA satoshi
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
|
|---|
| Keywords | スフィンゴ糖脂質 / ガングリオシド / 生活習慣病 / GM3ガングリオシド / レプチン / MC4R / NPC1L1 / 高コレステロール血症 / ガングリオシドGM3 / TLR4 / 慢性炎症 / マクロファージ / メタボリックシンドローム / GM3 / 筋分化 / GM3分子種 / 自然免疫活性化 / 超高分子量多量体 / インスリン抵抗性 |
|---|
| 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.
|
| 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。
|
