胆固醇和改变的孕激素代谢之间的关系在胎盘-母体肝脏双重体内
Paula Sanchon-Sanchez1, Elisa Herraez1, Rocio I R Macias1
1Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain.
胆固醇酶改变孕激素代谢酶,增加胎盘产量和降低妊娠肝脏胆固醇酶 (ICP) 的肝脏清除. 这种不平衡导致ICP患者的激素代谢物升高,并可能影响其他肝脏疾病.
科学领域:
- 肝病学和生殖内分泌学
- 生物化学和分子生物学
背景情况:
- 妊娠期肝脏内胆固醇症 (ICP) 的特征是母体血清胆酸,孕激素和硫酸代谢物水平升高.
- 一个关键的代谢物阿洛普雷格纳诺龙硫酸盐抑制了管功能,从而导致ICP病理生理学.
研究的目的:
- 调查胆固醇酶与在肝脏和胎盘中代谢孕激素的酶的表达/活性之间的关系.
- 阐明这些酶在ICP中观察到的改变激素环境中的作用.
主要方法:
- 在大鼠中通过胆道绑定 (BDL) 诱导的阻塞胆固醇.
- 定量逆转录PCR (RT-qPCR) 和西布洛特用于基因和蛋白质表达分析.
- 高性能液体染色学-并联质谱学 (HPLC-MS/MS) 用于酶活性测定.
主要成果:
- BDL降低了肝脏Srd5a1和Akr1c2的表达/活性,但在胎盘中增加了它们.
- ICP患者的胎盘显示SRD5A1 / AKR1C2升高,而胆固醇患者的肝活检显示表达减少.
- 酶表达没有通过Farnesoid X受体 (FXR) 激活或淘汰中介.
结论:
- 胆固醇酶显著改变SRD5A1和AKR1C2的表达,对胎盘 (上调) 和肝脏 (下调) 有相反的影响.
- 这些发现表明,ICP中孕激素代谢物升高的原因是胎盘产量增加和肝脏清除量减少.
- 降低肝清除也可能是其他胆固醇性肝病的机制.
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