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在与代谢功能障碍相关的脂肪肝炎中,FXR激活重塑肝脏和肠道转录景观
Ying-Quan Wen1,2, Zi-Yuan Zou2,3, Guan-Guan Zhao2,4
1School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
Acta pharmacologica Sinica
|July 11, 2024
概括
代谢功能障碍相关的脂肪肝炎 (MASH) 涉及复杂的转录性变化. 通过逆转代谢和炎症网络,FXR激活对MASH治疗具有前途,可能使三分之一的患者受益.
科学领域:
- 肝病学和代谢疾病研究.
- 转录学和分子生物学.
背景情况:
- 代谢功能障碍相关的脂肪肝炎 (MASH) 是一个日益严重的公共卫生问题.
- 法尔内索伊德X受体 (FXR) 激活是MASH的潜在治疗途径.
- 了解MASH的转录网络对于向治疗至关重要.
研究的目的:
- 为了阐明MASH相关的转录网络.
- 调查MASH中肝脏和肠道FXR激活的作用.
- 确定可能对FXR激动剂治疗有反应的患者群体.
主要方法:
- 来自人类和小鼠MASH模型的肝脏RNA-seq数据的分析.
- 用FXR激动剂治疗的小鼠和肝脏特异性FXR淘汰小鼠的转录组概况.
- 整合开源人类MASH数据集.
- 来自FXR调节小鼠的肠道RNA-seq数据的分析.
主要成果:
- 确定了关键的MASH转录干扰:代谢中断,线粒体功能障碍,修复减少,炎症增加和纤维化.
- 肝脏FXR激活通过逆转失调网络,解决纤维化和减少免疫细胞来改善MASH.
- 肠道FXR激活减少了肠道炎症,并显示了减轻肝炎和纤维化的潜力.
- 根据FXR网络相关性,鉴定出大约三分之一的MASH患者是FXR激动剂治疗的潜在候选人.
结论:
- FXR激活有效地逆转肝脏和肠道中关键的MASH转录失调.
- 在MASH病原和回归过程中,FXR起着至关重要的作用.
- 这些发现支持精确的药物开发和针对FXR向的MASH疗法的患者分层.
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