ERK/Cdk5軸は,PPARγγの糖尿病誘発作用を制御する
Alexander S Banks1, Fiona E McAllister2, João Paulo G Camporez3
1Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|November 20, 2014
まとめ
サイクリン依存キナーゼ5 (Cdk5) は通常,インスリン抵抗性を防ぐために細胞外信号調節キナーゼ (ERK) を抑制する. MEK/ERKを阻害すると,インスリン感受性が改善され,2型糖尿病の潜在的な治療法となる.
科学分野:
- メタボリック疾患の研究
- 分子内分泌学は分子内分泌学である.
- 糖尿病の病原性とは
背景:
- 肥満に起因するインスリン抵抗性は,2型糖尿病の先駆けです.
- Cdk5によるセリン273におけるペロキシソーム増殖器活性化受容体 γ (PPARγ) のリン酸化は,糖尿病性遺伝子発現を刺激する.
- PPARγを標的とする現在の抗糖尿病薬は,このリン酸化を阻害する.
研究 の 目的:
- 脂肪組織におけるCdk5がPPARγのリン酸化とインスリン抵抗性における役割を調査する.
- Cdk5.3が存在しない場合,PPARγセリン273のリン酸化に責任を負うキナーゼを特定する.
- 2型糖尿病の治療のために特定されたキナーゼ経路を標的とした治療の可能性を調査する.
主な方法:
- 脂肪特異的なCdk5除去を施したマウスの世代.
- ノックアウトマウスの活性化キナーゼを特定するためのプロテオミック分析.
- ERKによるPPARγの直接リン酸化を確認するためのインビボおよびインビトロ実験.
- 肥満マウスモデルにおけるMEKとERKの薬理学的阻害.
主要な成果:
- 逆説的にPPARγセリン273のリン酸化が増加し,インスリン抵抗性が悪化した.
- 細胞外信号調節キナーゼ (ERK) は,Cdk5除去されたマウスで活性化キナーゼとして識別されました.
- ERKはセルリン273でPPARγを直接リン酸化し,Cdk5はMEK経由でERKの活動を抑制する.
- MEK/ERKの薬理学的阻害は肥満マウスのインスリン抵抗性を有意に改善し,Cdk5の除去効果を救出しました.
結論:
- ERK/Cdk5シグナリング軸は,脂肪組織におけるPPARγ機能を決定的に調節する.
- ERK媒介によるPPARγのリン酸化は,インスリン抵抗性に寄与する.
- MEK/ERKシグナル伝達阻害剤は,2型糖尿病の有望な治療戦略です.
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