逆转PXR或PPARα激活诱导的肝病巨变
Yifei Zhang1, Jie Yang1, Shicheng Fan2
1Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Toxicology letters
|May 11, 2024
概括
由孕前X受体 (PXR) 或酶增殖器激活受体α (PPARα) 激活引起的肝脏扩大是可逆的. 抗激素的退出使肝脏大小,肝细胞特征和相关信号通路正常化.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 分子毒理学 分子毒理学
- 药理学 药理学是指药理学的学科.
背景情况:
- 孕妇X受体 (PXR) 和过氧体增殖器激活受体α (PPARα) 的激活可以导致肝脏扩大 (肝扩大).
- 之前的研究表明,这种肝病巨变涉及与YAP相关的蛋白质信号传递,导致肝细胞缩和增殖.
- 这种诱导的肝壮病在激动剂撤销后的可逆性以前没有确立.
研究的目的:
- 为了研究PXR或PPARα激活诱导的肝大病在撤销各自的激动剂后的回归.
- 为了确定肝脏大小,肝细胞特征和相关的分子信号通路是否恢复到正常水平.
主要方法:
- 使用的C57BL/6小鼠接受了PXR激活剂 (PCN) 或PPARα激活剂 (WY-14643) 的治疗.
- 使用免疫组织化学分析的抗原剂和分析肝脏组织.
- 与PXR/PPARα信号传递,肝细胞增殖和YAP信号传递相关的关键蛋白质的量化表达水平.
主要成果:
- 取消PCN或WY-14643导致肝脏大小回归到正常水平.
- 免疫组织化学显示,肝细胞缩的逆转和肝细胞增殖的减少.
- 下游目标PXR/PPARα,扩散标记物 (CCNA1,CCND1,PCNA) 和YAP信号蛋白 (CTGF,CYR61,ANKRD1) 的表达恢复到了基线水平.
结论:
- 激活PXR或PPARα诱导的肝壮病是一种可逆的疾病.
- 回归涉及肝细胞大小,增殖和YAP信号的正常化.
- 这些发现支持PXR和PPARα作为治疗药物点的潜在安全性.
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