The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

被引:1137
作者
Staudinger, JL
Goodwin, B
Jones, SA
Hawkins-Brown, D
MacKenzie, KI
Latour, A
Liu, YP
Klaassen, CD
Brown, KK
Reinhard, J
Willson, TN
Koller, BH
Kliewer, SA
机构
[1] GlaxoSmithKline, Dept Mol Endocrinol, Res Triangle Pk, NC 27709 USA
[2] GlaxoSmithKline, Dept Biosci Support, Res Triangle Pk, NC 27709 USA
[3] GlaxoSmithKline, Dept Mol Pharmacol, Res Triangle Pk, NC 27709 USA
[4] GlaxoSmithKline, Dept Metab Dis, Res Triangle Pk, NC 27709 USA
[5] GlaxoSmithKline, Dept Med Chem, Res Triangle Pk, NC 27709 USA
[6] Univ N Carolina, Dept Med, Curriculum Genet, Chapel Hill, NC 27599 USA
[7] Univ Kansas, Med Ctr, Dept Pharmacol & Toxicol, Kansas City, KS 66160 USA
关键词
D O I
10.1073/pnas.051551698
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16 alpha -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 7 alpha -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.
引用
收藏
页码:3369 / 3374
页数:6
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