Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTα-OSTβ in cholestasis in humans and rodents
Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTα-OSTβ in cholestasis in humans and rodents
复制标题
DOI：
10.1152/ajpgi.00539.2005
复制
发表时间：
2006-06-01
影响因子：
4.5
通讯作者：
Ballatori, Nazzareno
中科院分区：
文献类型：
--
作者：
Boyer, James L.;Trauner, Michael;Ballatori, Nazzareno
有机溶质转运体（OSTα - OSTβ）是一种新型的异聚体胆汁酸和固醇转运体，表达于回肠、肾脏和肝脏上皮细胞的基底外侧膜。为了确定在胆汁淤积性肝损伤后OSTα - OSTβ是否经历法尼醇X受体（FXR）依赖性的适应性调节，对原发性胆汁性肝硬化（PBC）患者以及大鼠和Fxr基因敲除及野生型小鼠在胆总管结扎（CBDL）后的mRNA和蛋白质表达水平进行了分析。与对照组相比，PBC患者肝脏中OSTα和OSTβ的mRNA分别增加了3倍和32倍，而在大鼠和小鼠进行CBDL后，肝脏中Ostα和Ostβ的表达也增加。相反，在Fxr基因敲除小鼠中，Ostα和Ostβ的mRNA表达普遍较低，并且与野生型小鼠相比，CBDL未能增强Ostα和Ostβ的表达。用鹅去氧胆酸（一种选择性FXR配体）处理24小时的HepG2细胞，其OSTα和OSTβ的mRNA及蛋白质水平较高。通过共聚焦显微镜在质膜上可观察到OST蛋白的增加。这些结果表明，Ostα和Ostβ的表达在胆汁淤积时受到高度调节，并且这种反应依赖于FXR胆汁酸受体。
Organic solute transporter (OST alpha-OST beta) is a novel heteromeric bile acid and sterol transporter expressed at the basolateral membranes of epithelium in the ileum, kidney, and liver. To determine whether OST alpha-OST beta undergoes farnesoid X receptor (FXR)-dependent adaptive regulation following cholestatic liver injury, mRNA and protein expression levels were analyzed in patients with primary biliary cirrhosis (PBC) and following common bile duct ligation (CBDL) in rats and Fxr null and wild-type mice. Hepatic OST alpha and OST beta mRNA increased 3- and 32- fold, respectively, in patients with PBC compared with controls, whereas expression of Ost alpha and Ost beta also increased in the liver of rats and mice following CBDL. In contrast, expression of Ost alpha and Ost beta mRNA was generally lower in Fxr null mice, and CBDL failed to enhance expression of Ost alpha and Ost beta compared with wild-type mice. HepG2 cells treated for 24 h with chenodeoxycholic acid, a selective FXR ligand, had higher levels of OST alpha and OST beta mRNA and protein. Increases in OST protein were visualized by confocal microscopy at the plasma membrane. These results indicate that expression of Ost alpha and Ost beta are highly regulated in response to cholestasis and that this response is dependent on the FXR bile acid receptor.