FXRの抑制は,ACE2を減少させることで,SARS-CoV-2感染から保護することができる
Teresa Brevini1, Mailis Maes2, Gwilym J Webb3
1Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK. tb647@cam.ac.uk.
Nature
|December 5, 2022
まとめ
ファーネソイドX受容体 (FXR) は,重要なSARS-CoV-2受容体であるアンジオテンシン変換酵素2 (ACE2) の発現を直接制御する. ウルソデオキシコール酸 (UDCA) は,ACE2を減少させ,COVID-19の感受性を低下させる可能性があります.
科学分野:
- 分子生物学
- ウイルス学
- 薬理学について
背景:
- アンジオテンシン変換酵素2 (ACE2) は,SARS-CoV-2の重要な宿主受容体である.
- ACE2発現を調節するメカニズムは完全に理解されていません.
- ACE2の調節は,COVID-19に対する潜在的な化学予防戦略を提供します.
研究 の 目的:
- ファーネソイドX受容体 (FXR) がACE2転写を調節する役割を調査する.
- ACE2のダウンレギュレーションとSARS-CoV-2の感受性の低下におけるFXR調節剤,特にウルソデオキシコール酸 (UDCA) の有効性を評価する.
主な方法:
- 関連するヒトおよび動物モデルにおけるACE2転写の直接レギュレータとしてFXRを調査した.
- オーガノイドと組織におけるFXRシグナル伝達とACE2発現を調節するためにz-ググルステロンとUDCAを使用した.
- SARS-CoV-2 感染感受性を in vitro,in vivo,および ex vivo で評価した.
- クリニカルレジストリデータと肝臓移植コホートを分析し,UDCA治療と臨床結果を相関させた.
主要な成果:
- FXRは複数の組織でACE2転写の直接的レギュレータとして特定されました.
- UDCAは,ヒトのオルガノイド,動物モデル,およびex vivoに浸透したヒト臓器におけるACE2発現を成功裏に減少させました.
- UDCA治療は,肝臓移植受容者を含む,SARS-CoV-2に感染した患者の臨床結果の改善と相関していました.
結論:
- FXRは,ACE2発現を制御する上で重要な役割を果たします.
- FXR-ACE2経路をUDCAで調節することで,SARS-CoV-2感染を軽減し,臨床結果を改善することが期待されています.
- COVID-19の治療介入としてUDCAを調査するためのさらなる臨床試験が必要である.
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