イノシトール-1,4,5-トリスホスファート受容体は,断食および糖尿病における肝臓グルコネオゲネシスを調節する
Yiguo Wang1, Gang Li, Jason Goode
1Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature
|April 13, 2012
まとめ
グルカゴンは,カルシウムシグナル伝達を活性化することによって,肝臓のグルコース生成を刺激し,CRTC2.2を脱酸化します. この経路は糖尿病では制御不能ですが,それをターゲットにすると,グルコースレベルが改善されます.
科学分野:
- 細胞生物学 細胞生物学
- メタボリック・レギュレーション
- ホルモンのシグナル伝達
背景:
- グルカゴンは,CRTC2脱酸化を含む循環AMP (cAMP) 経路経由で肝臓のグルコース生成を促進する.
- ホルモンシグナルとCRTC2のセル/スレリン酸塩酸塩による脱酸化を結びつける正確なメカニズムは,完全に理解されていません.
研究 の 目的:
- 肝細胞におけるグルカゴン媒介CRTC2脱酸化における細胞内カルシウム貯蔵とカルシヌーリンの役割を明らかにする.
- インスリンシグナル伝達によるこの経路の調節と糖尿病におけるその影響を調査する.
主な方法:
- マウス肝細胞での研究で,グルカゴンがカルシウム動員とCRTC2リン酸化に及ぼす影響を調べました.
- イノシトール-1,4,5-トリフォスファート受容体 (InsP(3) Rs),CRTC2,およびカルシヌーリンの間の相互作用を調査しました.
- インスリンシグナル伝達と糖尿病がInsP(3) R活動とグルコン生成に与える影響を評価した.
主要な成果:
- グルカゴンは,細胞内カルシウムを動員し,カルシネウリンを活性化することによって,肝細胞におけるCRTC2脱リン酸化を刺激する.
- このプロセスは,CRTC2に関連したInsP(3) RsのPKA媒介のリン酸化を伴い,グルコネオゲン遺伝子の発現を強化します.
- インスリンシグナル伝達がInsP(3) Rsを無効化し,食事中にCRTC2の活性が低下する. InsP(3) Rの活性が糖尿病で上昇する.
結論:
- グルカゴンはcAMPとカルシウムシグナル伝達軸を利用し,InsP(3) Rsとカルシヌーリンを巻き込み,肝臓のグルコース産生を調節する.
- 調節不良のInsP(3) R活動は,糖尿病におけるグルコネオゲネシスの上調に寄与する.
- 肝臓のInsP(3)Rsとカルシーヌーリンをターゲットにすることは,インスリン抵抗性および糖尿病に対する潜在的な治療戦略を提供します.
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