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FOXO1-PGC-1α相互作用によるインスリン調節肝臓グルコネオゲネシス
Pere Puigserver1, James Rhee, Jerry Donovan
1Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|May 20, 2003
まとめ
断食生存に不可欠な肝臓のグルコネオゲネシスは,FOXO1とPGC-1alphaによって調節されます. これらの要因は,インスリン調節による肝臓におけるグルコース産生を制御するために相互作用する.
科学分野:
- メタボリック調節 メタボリック調節
- 分子生物学は分子生物学である.
- エンドクリノロジー エンドクリノロジー
背景:
- 肝臓のグルコネオゲネシスは,断食中の生存に不可欠ですが,糖尿病では失調しています.
- グルココルチコイドとグルカゴンは肝臓のグルコネオゲネシスを刺激し,インスリンがそれを抑制する.
- FOXO1とPGC-1αは重要な調節因子ですが,その相互作用は不明でした.
研究 の 目的:
- 肝臓のグルコン生成の調節におけるFOXO1とPGC-1αの協力メカニズムを解明する.
- FOXO1-PGC-1α相互作用におけるAkt媒介のリン酸化の役割を調査する.
- FOXO1.1.経由でPGC-1α刺激によるグルコン生成にインスリンが与える影響を決定する.
主な方法:
- 細胞およびマウスモデルで野生型および変異FOXO1アレルを使用した.
- FOXO1.1のPGC-1α結合と共同活性化を研究した.
- 改変FOXO1.1の存在下でPGC-1α刺激によるグルコン生成に対するインスリン効果を評価した.
主要な成果:
- PGC-1alphaはFOXO1を結合し,同活性化させ,これはAktのリン酸化によって抑制されるプロセスである.
- FOXO1は,PGC-1α媒介によるグルコネ原性遺伝子発現誘導に不可欠である.
- インスリンによるPGC-1α誘発のグルコン生成の抑制は,インスリン不敏感FOXO1変異体によって逆転する.
結論:
- FOXO1とPGC-1αは,インスリン調節肝臓グルコネオゲネシスを実行するための重要な複合体を形成します.
- この相互作用は,グルコースの生産を制御するための重要な経路を強調しています.
- FOXO1-PGC-1αの相互作用をターゲットにすることで,代謝障害の治療戦略を提供することができる.
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