在肥胖患者中,FXR适应肝脏线粒体功能以增加基质氧化
Katrin Panzitt1,2,3, Emilian Jungwirth1,2,3,4, Lena E Vosko1
1Research Unit for Translational Nuclear Receptor Research, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria.
Science translational medicine
|August 13, 2025
概括
肥胖会改变胆酸受体FXR信号,影响肝脏新陈代谢. 肥胖酸激活FXR可提高肥胖个体的能量基质利用率和线粒体功能.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 代谢性疾病是一种代谢性疾病.
- 核受体信号传递的信号
背景情况:
- 核受体,包括胆酸受体Farnesoid X受体 (FXR),对营养状况敏感,并调节代谢途径.
- 肥胖与代谢失调有关,可能会改变FXR信号传递.
- 了解肥胖症中的FXR通路适应对于开发向疗法至关重要.
研究的目的:
- 在肥胖个体中定义FXR信号通路的代谢适应.
- 调查FXR激活对肝脏基因表达和肥胖中的代谢功能的影响.
- 针对肥胖和FXR激动剂治疗的反应来表征FXR DNA结合和转录性变化.
主要方法:
- 在肝活检样本上集成ChIP-seq (染色体免疫沉测序) 和RNA-seq (RNA测序) 的多原子分析.
- 肥胖和不肥胖个体之间的FXR结合和基因表达特征的比较.
- 用安慰剂或FXR激动剂obeticholic acid (OCA) 进行治疗.
主要成果:
- 在肥胖个体中,FXR占据了显著更多的DNA结合部位.
- 由OCA激活的FXR极大地改变了转录输出,特别是在肥胖个体中.
- 多原子数据的整合确定了线粒体功能和基质氧化作为由肥胖症中FXR激活调节的关键途径.
- 在肥胖患者中,FXR激活增强了β-氧化和氧化酸化,对抗了活性氧物种 (ROS) 生产,并使减少的谷氨水平正常化.
结论:
- 在肥胖患者中,FXR信号通路呈现出不同的特征,其特征是DNA结合和转录程序的改变.
- 肥胖症中的FXR激活增强了能量基质利用率,并改善了线粒体功能.
- 准FXR信号是一种潜在的治疗策略,用于治疗肥胖的代谢失调.
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