栄養素を感知する核受容体は,オートファギーを調整する

Jae Man Lee¹, Martin Wagner¹, Rui Xiao¹

¹Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

Nature

|November 11, 2014

まとめ

栄養素受容体PPARαとFXRは肝臓のオートファギーを制御する. PPARαは栄養状態でオートファギーを促進し,FXRは断食状態でそれを抑制し,重要な転写調節機構を明らかにします.

科学分野:

細胞生物学細胞生物学
メタボリズムは
分子内分泌学分子内分泌学

背景:

オートファギーは,栄養素のリサイクルとエネルギーホメオスタシスのための保存されたプロセスです.
オートファギーの急性調節は理解されているが,長期的な転写制御は不明である.
核受容体PPARα (断食肝) とFXR (栄養肝) は,重要な栄養センサーである.

研究の目的:

ネズミにおける肝臓オートファギーの転写制御におけるPPARαとFXRの役割を調査する.
これらの核受容体が栄養状態 (断食 vs. 給餌) に応じて自己消化を調節する方法を解明する.

主な方法:

野生型のマウスのPPARαとFXRの薬理学的活性化を活用した.
機能的な役割を評価するために,ノックアウトマウスモデル (Ppara(-/-) とFxr(-/-)) を採用した.
プロモーター結合とオートファジーに関連する遺伝子発現を調べることで,転写調節を分析した.

主要な成果:

PPARαの活性化により,栄養状態のオートファギーの抑制が逆転し,リポファギーを誘発し,これはPpara(-/-) マウスでは存在しない反応である.
FXRの活性化により,空腹状態のオートファギーの誘発が抑制され,Fxr(-/-) マウスでは応答は存在しなかった.
PPARαとFXRは,共有されたオートファジック遺伝子プロモーターに結合し,対極的な転写効果を発揮するために競合することが判明しました.

結論:

PPARαとFXRは肝臓のオートファギーの重要な調節体であり,栄養素の利用可能性に反応する.
これらの受容体は,栄養状態に基づいたオートファギーの制御のための補完的で相互に絡み合う転写メカニズムを提供します.
発見は,急性信号伝達経路を超えて,オートファギーの長期的な調節に関する新しい洞察を明らかにします.

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