Bile acids, key compounds for the mechanistic analyses of hepatotoxicity, and nuclear receptor interaction

饲粮中添加1%石胆酸（LCA） 5 ~ 9 d后，fxr阴性和野生型雌性小鼠肝损伤标志物谷草转氨酶（AST）和碱性磷酸酶（ALP）活性均升高。野生型小鼠的水平明显高于无fxr小鼠。与肝毒性标志物活性一致，在添加1% LCA后，野生型小鼠的血清和肝脏胆汁酸水平，特别是LCA和tauroLCA，明显高于FXR-null小鼠。fxr缺失小鼠肝脏中LCA（5.5倍）和羟基类固醇硫转移酶St2a（5.8倍）的硫酸化活性显著升高。饲喂LCA的无fxr小鼠胆囊胆汁中3a-硫酸胆汁酸浓度比野生型小鼠高7.4倍。这些结果表明，由羟基类固醇硫转移酶催化的LCA硫酸化至少是一种保护LCA诱导的肝损伤的途径。此外，对FXR-null、PXR-null和FXR-PXR双空小鼠的northern blot分析表明，这些核受体对St2a的基础表达具有抑制作用。fxr缺失小鼠对胆酸（CA）诱导的肝毒性高度敏感。饲粮添加0.25%钙后，谷草转氨酶活性升高15.7倍，而饲粮添加0.25%钙和1%钙的野生型小鼠血清谷草转氨酶活性仅略微升高1.7倍和2.5倍。饲喂0.25和1.0% CA的野生型小鼠胆汁酸输出率分别提高了2.0倍和3.7倍。另一方面，饲喂0.25% CA的无fxr小鼠的胆汁酸输出率没有显著增加，而饲喂1.0% CA的小鼠的胆汁酸输出率则显著降低，尽管肝牛磺酸共轭胆汁酸水平明显升高。这些结果表明，ca诱导的小管胆汁酸输出率的增强参与了预防ca诱导的毒性的适应性反应。少

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 (AST) and alkaline phosphatase (ALP) activities in both FXR-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and tauroLCA, 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 St2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3a-sulfated bile acid concentration was observed in gallbladder bile of FXR-null mice fed a LCA diet compared to that of wild-type mice. These results indicate that LCA sulfation catalyzed by hydroxysteroid sulfotransferase is at least one pathway for protection against LCA-induced liver damage. Further … More more, northern blot analysis using FXR-null, PXR-null and FXR-PXR double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression.FXR-null mice are highly sensitive to cholic acid (CA)-induced liver toxicity. AST activity was elevated 15.7-fold after feeding a 0.25% CA diet, whereas only slight increases in serum AST (1.7-fold and 2.5-fold) were observed in wild-type mice fed 0.25% and 1% CA diet, respectively. The bile acid output rate was 2.0-fold and 3.7-fold higher after feeding of 0.25 and 1.0% CA diet in wild-type mice, respectively. On the other hand, no significant increase in bile acid output rate was observed in FXR-null mice fed 0.25% CA diet in contrast to a significant decrease observed in mice fed a 1.0% CA diet in spite of the markedly higher levels of hepatic tauro-conjugated bile acids. These results suggest that the CA-induced enhancement of canalicular bile acid output rate is involved in adaptive responses for prevention of CA-induced toxicity. Less