Role of farnesoid X receptor in the enhancement of canalicular bile acid output and excretion of unconjugated bile acids: A mechanism for protection against cholic acid-induced liver toxicity
Role of farnesoid X receptor in the enhancement of canalicular bile acid output and excretion of unconjugated bile acids: A mechanism for protection against cholic acid-induced liver toxicity
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DOI：
10.1124/jpet.104.076158
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Yamazoe, Y
中科院分区：
文献类型：
--
作者：
Miyata, M;Tozawa, A;Yamazoe, Y
缺乏参与维持肝胆汁酸水平的法尼醇X受体（FXR）的小鼠对胆酸诱导的肝毒性高度敏感。喂食0.25%胆酸饲料后，血清天冬氨酸转氨酶（AST）活性升高15.7倍，而在喂食0.25和1%胆酸饲料的野生型小鼠中分别观察到血清AST仅轻微升高（1.7和2.5倍）。胆盐输出泵mRNA和蛋白质水平在喂食1%胆酸饮食的野生型小鼠中增加（2.1倍和3.0倍），但在喂食0.25%胆酸饮食的FXR缺失小鼠中降低。在野生型小鼠中，饲喂0.25%和1.0%胆酸饲料后，胆汁酸排出率分别高出2.0倍和3.7倍。另一方面，在喂食0.25%胆酸饲料的FXR缺失小鼠中未观察到胆汁酸排出率显著增加，而在喂食1.0%胆酸饲料的小鼠中观察到胆汁酸排出率显著降低，尽管肝牛磺结合胆汁酸水平显著较高。在喂食对照饲料的野生型小鼠的胆汁中未检测到未结合胆酸，但在喂食1%胆酸饲料的野生型小鼠中很容易检测到。在肝牛磺酸耗竭条件下，胆汁非结合胆酸与总胆酸（非结合胆酸和牛磺结合胆酸）的比例达到30%。这些结果表明，胆酸诱导的小管胆汁酸输出率和未结合胆汁酸排泄的增强参与了预防胆酸诱导的毒性的适应性反应。
Mice lacking the farnesoid X receptor (FXR) involved in the maintenance of hepatic bile acid levels are highly sensitive to cholic acid-induced liver toxicity. Serum aspartate aminotransferase (AST) activity was elevated 15.7-fold after feeding a 0.25% cholic acid diet, whereas only slight increases in serum AST (1.7- and 2.5-fold) were observed in wild-type mice fed 0.25 and 1% cholic acid diet, respectively. Bile salt export pump mRNA and protein levels were increased in wild-type mice fed 1% cholic acid diet (2.1- and 3.0-fold) but were decreased in FXR-null mice fed 0.25% cholic acid diet. The bile acid output rate was 2.0- and 3.7-fold higher after feeding of 0.25 and 1.0% cholic acid 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% cholic acid diet in contrast to a significant decrease observed in mice fed a 1.0% cholic acid diet in spite of the markedly higher levels of hepatic tauro-conjugated bile acids. Unconjugated cholic acid was not detected in the bile of wild-type mice fed a control diet, but it was readily detected in wild-type mice fed 1% cholic acid diet. The ratio of biliary unconjugated cholic acid to total cholic acid ( unconjugated cholic acid and tauro-conjugated cholic acid) reached 30% under conditions of hepatic taurine depletion. These results suggest that the cholic acid-induced enhancement of canalicular bile acid output rates and excretion of unconjugated bile acids are involved in adaptive responses for prevention of cholic acid-induced toxicity.