| Project/Area Number |
18K11006
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 59040:Nutrition science and health science-related
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| Research Institution | Kindai University |
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Principal Investigator |
TANAKA Yuji 近畿大学, 大学病院, 講師 (00465650)
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| Co-Investigator(Kenkyū-buntansha) |
上硲 俊法 近畿大学, 大学病院, 教授 (20233934)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | 胆汁鬱滞 / 総胆管結紮 / 脂質代謝異常 / 小腸 / コレステロールトランスポーター / TICE / エゼチミブ / ペマフィブラート / ABCG5/G8 / NPC1L1阻害剤 |
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| Outline of Final Research Achievements |
Any excessive cholesterol is transported back to the liver from the peripheral tissues and excreted in bile. In addition to the biliary route, transintestinal cholesterol efflux (TICE), a mechanism wherein cholesterol enters the small intestinal epithelial cells from the blood and is directly excreted into the intestinal lumen, was recently reported as a route of cholesterol excretion. In the present study, drug-induced cholestasis and bile duct ligation (BDL) induced intestinal expression of LDL receptor as well as Abcg5/g8 and enhanced fecal cholesterol excretion. Similarly, TICE pathway can be stimulated by lipid-lowering drugs ezetimibe and pemafibrate by increasing intestinal cholesterol efflux transporters Abcg5/g8. Furthermore, pemafibrate may suppress intestinal cholesterol absorption by reducing NPC1L1 and SR-B1. These data indicated that the small intestine may be a target organ for the prevention of atherosclerosis.
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| Academic Significance and Societal Importance of the Research Achievements |
これまで如何なる分子がTICEを担うか一定の結論は得られていない。本研究では総胆管を結紮する動物モデルで小腸LDLレセプターとAbcg5/g8の増加およびTICEの亢進が確認された。この結果からLDLレセプターによる小腸上皮細胞内への取り込みとAbcg5/g8による腸管への排泄がTICEの中心分子機構と考えられた。さらに高脂血症治療薬の投与によりAbcg5/g8を介してTICEが増強したことから小腸を標的とした動脈硬化予防の可能性が示唆された。
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