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肝臓におけるPPARααに対する生理学的に重要な内生性リガンドの特定
Manu V Chakravarthy1, Irfan J Lodhi, Li Yin
1Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Cell
|August 4, 2009
まとめ
脂肪酸合成酵素 (FAS) は,リンパ脂,1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC) を生成するのに役立ち,これは核受容体PPARalphaの内生リガンドとして作用し,脂質代謝に影響を与えます.
科学分野:
- バイオケミストリー バイオケミストリー
- 分子生物学は分子生物学である.
- メタボリック疾患
背景:
- 核受容体PPARalphaは,脂質代謝障害に対する薬物標的である.
- PPARalphaの内生リガンドは未確認のままである.
- 脂肪酸合成酵素 (FAS) の不活性化により,PPARαα依存遺伝子の発現が損なわれ,リガンド生成におけるその役割が示唆される.
研究 の 目的:
- PPARalphaの内生リガンドを特定するために.
- PPARアルファリンガンド生成における脂肪酸合成酵素 (FAS) の役割を調査する.
- 特定されたリガンドがPPARalphaと相互作用し,遺伝子発現と肝臓ステアトーシスに与える影響を特徴づける.
主な方法:
- マウスの肝臓からPPARalphaに結合したフォスフォリピドの分離と分析.
- 結合したフォスフォリピドの種を特定するための質量スペクトロメトリ.
- フォスファディチルコリン合成酵素のノックダウン後の遺伝子発現分析 (Cept1).
- PPARalpha,PPARdelta,PPARgammaを用いたインビトロ結合測定法について.
- 特定されたリガンドのポータル静脈注入を含むin vivo研究.
主要な成果:
- フォスフォリピドである1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC) は,マウスの肝臓でPPARalphaに結合していることが確認されました.
- FASの活動は,PPARalphaに結合した16:0/18:1-GPCの存在と相関する.
- フォスファディチルコリン合成酵素であるCept1のノックダウンにより,PPARαα依存遺伝子発現が低下した.
- 16:0/18:1-GPCは,PPARalphaと強力な相互作用を示し,既知のアゴニストと比べられる.
- 16:0/18:1-GPCの注入により,PPARアルファ依存遺伝子発現が活性化され,肝臓ステアトーシスが in vivoで減少しました.
結論:
- 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC) は,PPARalpha.comの生理学的に関連する内生リンガンドである.
- 脂肪酸合成酵素 (FAS) とフォスファディチルコレンの合成は,このPPARアルファリンガンドを生成するために不可欠です.
- この発見は,脂質代謝の調節に関する新しい洞察と,PPARalpha.を標的とした潜在的な治療戦略を提供します.
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