ケトン・ボディ・シグナリング 腸幹細胞の恒常状態と食事への適応を媒介する
Chia-Wei Cheng1, Moshe Biton2, Adam L Haber3
1Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
Cell
|August 24, 2019
まとめ
ベータ・ヒドロキシブチラート (βOHB) のようなケトン体は,腸の幹細胞 (ISC) 機能に不可欠です. 食事はβOHBレベルに影響し,組織修復のためのISCの自己再生と分化に影響します.
科学分野:
- メタボロミクス
- 幹細胞生物学
- 胃腸内科
背景:
- メタボライトは組織特異的な幹細胞の機能と生理を調節する上で重要な役割を果たします.
- 代謝産物と腸の幹細胞 (ISC) の行動を結びつける特定のメカニズムは十分に理解されていません.
研究 の 目的:
- 哺乳類の小腸幹細胞機能における,3-ヒドロキシ-3-メチルグルタリル-コア合成酵素2 (Hmgcs2) とその産物β-ヒドロキシブチラート (βOHB) の作用を調査する.
- βOHBがISCの自己再生,分化,食事の変化への反応にどのように影響するか解明する.
主な方法:
- Lgr5+ ISCにおけるHmgcs2発現の分析と分化腸内細胞の比較
- Hmgcs2遺伝子操作後のISCにおけるβOHBレベルの評価
- 外因的なβOHBおよびクラスIヒストン脱酸化酵素 (HDAC) 阻害剤を用いた救出実験.
- 異なる食事条件下でのISC機能と再生の評価 (ケトゲン対グルコース補給)
主要な成果:
- Hmgcs2発現は,自己再生するLgr5+ISCを他の腸内細胞タイプと区別する.
- Hmgcs2の損失は,ISCにおけるβOHBを減少させ,分泌器の分化に歪みをもたらす.
- 外因的なβOHBおよびHDAC阻害剤は,差別化フェノタイプを救済する.
- βOHBはHDACを阻害し,ISCの自己更新と系統決定に不可欠なNotchシグナリングを強化します.
- ケトジェニックなダイエットはβOHB媒介のNotchシグナル伝達によってISCの機能と再生を高め,グルコース補給されたダイエットは逆効果を発揮する.
結論:
- ベータ・ヒドロキシブチレート (βOHB) は,腸の幹細胞 (ISC) の自己再生と分化を調節する重要な代謝物質である.
- 食事による摂取は,βOHBレベルと関連するシグナル伝達経路の調節によって,ISC機能と腸の再生に有意な影響を及ぼします.
- βOHB活性化されたシグナリングをターゲットにすることは,腸内ホメオスタシスと損傷における幹細胞適応を調節するための潜在的な戦略です.
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