在多微生物性败血症中,HNF4α有助于肝脏CAR功能障碍
Céline Van Dender1,2, Steven Timmermans1,2, Maxime Roes1,2
1Center for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium.
Frontiers in immunology
|September 4, 2025
概括
败血症会损害构成性安德罗斯坦受体 (CAR) 的肝功能,影响药物代谢和生存. 针对HNF4α等上游调节剂可能比CAR本身更有效治疗败血症.
科学领域:
- 肝病学和分子内分泌学
- 败血症病理生理和新陈代谢
背景情况:
- 构成性安德罗斯坦受体 (CAR) 调节肝脏代谢,是肝脏疾病的潜在治疗点.
- 在毒症中CAR的作用,这是一种危及生命的疾病,药物代谢和肝功能发生变化,目前还没有得到充分的研究.
- 假设:在败血症期间,CAR功能受损,影响肝脏过程.
研究的目的:
- 在败血症期间调查肝脏中CAR的功能状态.
- 阐明毒症中CAR功能障碍背后的分子机制.
- 评估毒症中针对CAR的治疗潜力.
主要方法:
- 血症模型诱导和使用CAR激动剂 (TCPOBOP) 和抑制剂 (CINPA1).
- 对*Nr1i3*mRNA表达,HNF4α与*Nr1i3*促进体结合以及Ppara表达的分析.
- 评估与新陈代谢和急性阶段反应相关的CARDNA结合,染色质可访问性和基因表达.
主要成果:
- 在败血症期间,肝脏的CAR功能显著下降,TCPOP的反应有所减少.
- 败血症通过降低HNF4α结合和降低Ppara表达来降低*Nr1i3*转录,从而损害CAR DNA结合.
- 在败血症中,CAR功能丧失导致代谢基因表达的改变和急性反应,但抑制CAR会使败血症的致死性恶化.
结论:
- 在败血症期间,CAR在维持肝脏新陈代谢,再生和生存方面发挥着至关重要的作用.
- 在败血症中,CAR迅速下调,使其成为不太可能的治疗点;像HNF4α这样的上游调节剂需要进一步调查.
- 向HNF4α可能是治疗败血症的更有前途的策略.
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