脂肪酸の炭素は,内皮細胞のdNTP合成に不可欠である
Sandra Schoors1,2, Ulrike Bruning1,2, Rindert Missiaen1,2
1Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, B-3000, Belgium.
Nature
|April 2, 2015
まとめ
内皮細胞は,血管の芽生えの間に増殖するために脂肪酸酸化 (FAO) を必要とします. FAOのブロックは,核酸合成を阻害し,DNA複製と血管新生を妨げます.
科学分野:
- 細胞生物学 細胞生物学
- メタボリック研究
- 血管生物学 血管生物学
背景:
- 血管の発芽中の内皮細胞の代謝はよく理解されていません.
- 脂肪酸酸化 (FAO) は重要な代謝経路であり,血管新生における役割は不明である.
研究 の 目的:
- 速度を制限するFAO酵素であるカルニチンパルミトイルトランスフェラーゼ1A (CPT1A) が,内皮細胞の代謝と機能における役割を調査する.
- 障害のあるFAOが,内皮細胞の増殖,移動,DNA合成に与える影響を決定する.
主な方法:
- 人間とネズミの内皮細胞におけるCPT1Aの遺伝子静止を活用した.
- 代謝経路を追跡するために,イソトープラベル付けの研究を採用した.
- 細胞の増殖,移動,およびニュクレオチド合成を評価した.
- マウスモデルでの病的な眼球血管新生に対するCPT1A阻害の影響を調査した.
主要な成果:
- CPT1Aの内皮喪失は内皮細胞の増殖を阻害するが,移動を阻害せず,血管芽生え障害を引き起こす.
- 減少したFAOはエネルギー枯渇や酸化還元不均衡をもたらさなかったが,新規の核酸合成を阻害した.
- 脂肪酸の炭素はクレブス循環と核酸前駆体に組み込まれ,DNA複製をサポートしました.
- CPT1Aは,アスパルタ酸とデオキシリボヌクレオシドトリフォスファートが枯渇し,アセテートまたはヌクレオシドが現象型を救った.
- CPT1阻害は,マウスの病理的な眼球血管新生を抑制しました.
結論:
- CPT1A媒介のFAOは,DNA複製のためのヌクレオチド前駆体を提供することによって,内皮細胞の増殖に不可欠です.
- CPT1の封鎖を通してFAOをターゲットにすることは,病的な血管新生を抑制するための潜在的な治療戦略です.
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