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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype
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Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype

机译：妊娠肝内胆汁淤积症的硫酸化孕酮代谢物水平抑制法呢素X受体，导致胆汁淤积表型

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摘要

Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here we report that the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, coadministration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR, resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis.
机译：妊娠肝内胆汁淤积症（ICP）是最常见的妊娠特异性肝病，与胎儿不良结局（包括早产和子宫内死亡）的风险增加相关。引起胆汁淤积的内分泌信号尚不清楚，但已证明ICP中3α-硫酸化的孕酮代谢物升高，这使我们研究了硫酸化的孕酮代谢物对法呢素X受体（FXR）介导的胆汁酸稳态途径的影响。在这里，我们报道ICP患者的血清中3β-硫酸化的孕酮代谢物表阿普格雷醇硫酸盐被超生理学升高。胆酸攻击的小鼠发展为高胆固醇血症，并且肝基因表达谱表明FXR激活。然而，将硫酸表阿普列萘酮硫酸盐与胆酸共同给药会加重高胆固醇血症，并导致与胆汁淤积一致的肝胆酸反应性基因的异常基因表达谱。我们证明在ICP中发现的硫酸硫酸表果烷醇酮水平可以作为FXR的部分激动剂，从而导致肝癌细胞系和原代人肝细胞中胆汁酸稳态基因的异常表达。此外，硫酸表没食子甾烷醇酮对FXR的抑制导致FXR介导的胆汁酸流出减少和分泌的FGF19。使用辅因子募集测定，我们显示硫酸表阿普萘酮硫酸盐竞争性抑制胆汁酸介导的辅因子基序募集到FXR-配体结合域。结论：我们的研究结果揭示了ICP相关水平的3β硫酸化孕酮代谢物硫酸表阿普萘醇硫酸盐和FXR之间的新型分子相互作用，从而使ICP中妊娠的内分泌成分与异常胆汁酸稳态耦合。

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