核受体PXR是一种石胆酸传感器，可预防肝脏毒性。
The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.
作者信息
Staudinger J L, Goodwin B, Jones S A, Hawkins-Brown D, MacKenzie K I, LaTour A, Liu Y, Klaassen C D, Brown K K, Reinhard J, Willson T M, Koller B H, Kliewer S A
机构信息
Department of Molecular Endocrinology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
出版信息
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3369-74. doi: 10.1073/pnas.051551698.
The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.
孕烷X受体（PXR）是诸如孕烯醇酮16α-腈（PCN）等抗毒甾体的分子靶点，PCN可诱导细胞色素P450 3A（CYP3A）表达并保护机体免受有害化学物质的侵害。在本研究中，我们证明PXR可被毒性胆汁酸石胆酸（LCA）及其3-酮代谢产物激活。此外，我们表明PXR可调节参与胆汁酸生物合成、转运和代谢的基因表达，包括胆固醇7α-羟化酶（Cyp7a1）和Na⁺非依赖性有机阴离子转运体2（Oatp2）。最后，我们证明PXR的激活可预防LCA诱导的严重肝损伤。基于这些数据，我们提出PXR作为LCA的生理传感器，并协调调节基因表达以降低这种毒性胆汁酸的浓度。这些发现表明PXR激动剂可能在人类胆汁淤积性肝病的治疗中有用。
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