Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity
Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity
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DOI：
10.1074/jbc.m210634200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Yamazoe, Y
中科院分区：
文献类型：
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作者：
Kitada, H;Miyata, M;Yamazoe, Y
在饲料中补充1%石胆酸(LCA)5-9天后，法尼类X受体(FXR)阴性和野生型雌性小鼠肝损伤标志物天冬氨酸氨基转移酶和碱性磷酸酶活性均升高。野生型小鼠的水平明显高于FXR缺失型小鼠，尽管后者胆盐输出泵的表达减少。与肝脏毒性标记物活性一致，补充1%LCA后，野生型小鼠的血清和肝脏胆汁酸水平明显高于FXR缺陷型小鼠，尤其是LCA和牛磺酸胆石酸。在FXR基因缺失小鼠的肝脏中，LCA的硫酸盐化活性(5.5倍)和羟基类固醇磺基转移酶(ST)2a(5.8倍)显著增加。与野生型小鼠相比，饲喂LCA饲料的FXR基因缺失小鼠的胆汁中3α-硫酸盐胆汁酸浓度增加了7.4倍。肝脏St2a含量与碱性磷酸酶水平呈负相关。相反，与野生型小鼠相比，FXR基因缺失小鼠的微粒体Lca 6β羟化水平并没有增加，而且实际上更低。在LCA喂养的小鼠中，编码牛磺胆酸钠共转运多肽、有机阴离子转运多肽1和肝脏特异性有机阴离子转运体1功能的mRNA在胆汁酸输入中明显减少。补充1%LCA后，FXR基因缺失小鼠的这些转运蛋白水平高于野生型小鼠。MRP2、MRP3和MRP4mRNAs无明显变化。这些结果表明，羟基类固醇磺酸转移酶介导的LCA硫化是保护LCA诱导的肝损伤的主要途径。此外，对FXR缺失、孕烷X受体缺失和FXR孕烷X受体双缺失小鼠的Northern印迹分析表明，这些核受体对基础St2a的表达具有抑制作用。
Supplement of 1% lithocholic acid (LCA) in the diet for 5-9 days resulted in elevated levels of the marker for liver damage aspartate aminotransferase and alkaline phosphatase activities in both farnesoid X receptor (FXR)-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice, despite the diminished expression of a bile salt export pump in the latter. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and taurolithocholic acid, were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement. Marked increases in hepatic sulfating activity for LCA (5.5-fold) and hydroxysteroid sulfotransferase (St) 2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3alpha-sulfated bile acid concentration was observed in bile of FXR-null mice fed an LCA diet compared with that of wild-type mice. Liver St2a content was inversely correlated with levels of alkaline phosphatase. In contrast, microsomal LCA 6beta-hydroxylation was not increased and was in fact lower in FXR-null mice compared in wild-type mice. Clear decreases in mRNA encoding sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide 1, and liver-specific organic anion transporter-1 function in bile acid import were detected in LCA-fed mice. These transporter levels are higher in FXR-null mice than wild-type mice after 1% LCA supplement. No obvious changes were detected in the Mrp2, Mrp3, and Mrp4 mRNAs. These results indicate hydroxysteroid sulfotransferase-mediated LCA sulfation as a major pathway for protection against LCA-induced liver damage. Furthermore, Northern blot analysis using FXR-null, pregnane X receptor-null, and FXR-pregnane X receptor double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression.