Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase
Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase
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DOI：
10.2133/dmpk.21.315
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发表时间：
2006-01-01
影响因子：
2.1
通讯作者：
Yamazoe, Yasushi
中科院分区：
文献类型：
--
作者：
Miyata, Masaaki;Matsuda, Yoshiki;Yamazoe, Yasushi
羟基类固醇磺基转移酶催化胆汁酸硫酸化在对抗石胆酸（LCA）诱导的肝毒性中起重要作用。在法尼醇X受体缺失小鼠中，Sult 2a的肝脏水平比野生型小鼠高8倍。因此，在FXR缺失和野生型小鼠中检查了FXR配体（鹅去氧胆酸（CDCA）和LCA）喂养对肝Sult 2a表达的影响。在喂食LCA（1%和0.5%）饲料的FXR-null和野生型小鼠中，肝脏Sult 2a蛋白含量升高。用0.5%CDCA饮食治疗使野生型小鼠的肝Sult 2a降低至对照的20%，但增加了FXR缺失小鼠的含量。喂食CDCA饲料后，野生型小鼠的肝脏Sult 2a 1（St 2a 4）mRNA水平降低至26%，而喂食CDCA后，未观察到FXR基因敲除小鼠的Sult 2a 1 mRNA水平降低。肝脏Sult 2a蛋白含量与SHP mRNA水平呈显著负相关（r（2）= 0.523）。在野生型小鼠中，PCN介导的Sult 2a蛋白水平的增加通过CDCA喂养而减弱，但在FXR缺失小鼠中没有。在用FXR激动剂CDCA或GW 4064处理的HepG 2细胞中，人SULT 2A 1蛋白和mRNA水平以剂量依赖性方式降低，尽管SHP mRNA水平增加。这些结果表明，SULT 2A在小鼠和人类中通过CDCA介导的FXR活化受到负调控。
Hydroxysteroid sulfotransferase catalyzing bile acid sulfation plays an essential role in protection against lithocholic acid (LCA)-induced liver toxicity. Hepatic levels of Sult2a is up to 8-fold higher in farnesoid X receptor-null mice than in the wild-type mice. Thus, the influence of FXR ligand (chenodeoxycholic acid (CDCA) and LCA) feeding on hepatic Sult2a expression was examined in FXR-null and wild-type mice. Hepatic Sult2a protein content was elevated in FXR-null and wild-type mice fed a LCA (1% and 0.5%) diet. Treatment with 0.5% CDCA diet decreased hepatic Sult2a to 20% of the control in wild-type mice, but increased the content in FXR-null mice. Liver Sult2a1 (St2a4) mRNA levels were reduced to 26% in wild-type mice after feeding of a CDCA diet, while no decrease was observed on Sult2a1 mRNA levels in FXR-null mice after CDCA feeding. A significant inverse relationship (r(2) = 0.523) was found between hepatic Sult2a protein content and small heterodimer partner (SHP) mRNA level. PCN-mediated increase in Sult2a protein levels were attenuated by CDCA feeding in wild-type mice, but not in FXR-null mice. Human SULT2A1 protein and mRNA levels were decreased in HepG2 cells treated with the FXR agonists, CDCA or GW4064 in dose-dependent manners, although SHP mRNA levels were increased. These results suggest that SULT2A is negatively regulated through CDCA-mediated FXR activation in mice and humans.