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在多微生物败血症相关的代谢重编程和死亡中,HNF4α的关键作用

Céline Van Dender^1,2, Steven Timmermans^1,2, Ville Paakinaho³

¹Center for Inflammation Research, VIB, Ghent, Belgium.

EMBO molecular medicine

|September 11, 2024

概括

败血症通过降低肝细胞核因子4α (HNF4α) 来损害肝功能,导致代谢问题和生存率降低. 恢复HNF4α活性为败血症提供了潜在的治疗策略.

科学领域:

肝病学肝病学是一种肝病学.
分子生物学分子生物学
败血症病理生理学病理生理学

背景情况:

败血症会引发饥饿反应,影响能量代谢.
肝脏氧酶增殖器激活受体α (PPARα) 的表达在败血症下降,损害脂肪酸代谢.
在败血症中PPARα下调的上游机制仍然不清楚.

研究的目的:

研究肝细胞核因子4α (HNF4α) 在败血症引起的代谢功能障碍中的作用.
阐明在败血症期间将HNF4α与PPARα调节联系在一起的机制.
评估向HNF4α在败血症中的治疗潜力.

主要方法:

在败血症模型中分析肝脏HNF4α表达和功能.
评估HNF4α耗尽对败血症结局的影响,包括致死率,肥胖症和器官损伤.
评估HNF4α调制对IL6介导的急性相应反应的影响.
在败血症模型中测试HNF4α激动剂的疗效.

主要成果:

败血症会导致肝脏HNF4α的功能逐渐丧失.
HNF4α对PPARα和其他核受体的表达至关重要.
缺少HNF4α会加剧败血症的死亡率,肥胖症和器官损伤.
缺少HNF4α会损害肝脏再生和生存所必需的IL6反应.
一种HNF4α激动剂证明了对败血症的保护作用,无论细菌负载如何.

结论:

在败血症期间,肝脏HNF4α活性显著降低.
降低HNF4α导致PPARα下调,代谢障碍和急性阶段反应受损.
HNF4α在败血症耐受性方面发挥着至关重要的作用,是有前途的治疗点.

关键词:

急性阶段反应失败的失败在 HNF4α 功能障碍下,肝脏肝脏肝脏肝脏由PPARα介导的脂质功能障碍败血症这是一种败血症.

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