The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp
The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp
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DOI：
10.1053/gast.2001.25503
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发表时间：
2001-07-01
期刊：
影响因子：
29.4
通讯作者：
Karpen, SJ
中科院分区：
文献类型：
--
作者：
Denson, LA;Sturm, E;Karpen, SJ
背景与目的：肝脏胆汁酸稳态是通过负反馈抑制参与胆汁酸摄取和合成的基因来调节的。胆汁酸通过胆汁酸受体(FXR)激活抑制性核受体Shp，下调胆汁酸合成的限速基因--胆固醇7α-羟基酶(Cyp7a)。我们假设Shp还将介导对主要的肝脏胆汁酸转运体NTCP的负反馈调节。方法：用维甲酸处理大鼠原代肝细胞或转染的HepG2、Cos细胞，观察其对胆汁酸转运、ntcp、shp基因表达及启动子活性的影响。使用合成的Fry、RXR和RAR蛋白进行凝胶位移分析。结果：胆汁酸处理大鼠原代肝细胞可抑制视黄醇激活ntcp基因的表达和功能，这与shp基因的激活在时间上是一致的。胆汁酸介导的下调是通过依赖FXR抑制ntcp RXR：RAR反应元件发生的。此外，共转染shp可直接抑制ntcp启动子的维甲酸激活。结论：胆汁酸激活的FXR通过诱导SHP对NTCP进行负反馈调节。这种新的调控途径提供了一种协同下调胆汁酸输入和合成的方法，从而在胆汁淤积条件下保护肝细胞免受胆汁酸介导的损伤。
Background & Aims: Hepatic bile acid homeostasis is regulated by negative feedback inhibition of genes involved in the uptake and synthesis of bile acids. Bile acids down-regulate the rate-limiting gene for bile acid synthesis, cholesterol 7 alpha -hydroxylase (cyp7a), via bile acid receptor (fxr) activation of an inhibitory nuclear receptor, shp. We hypothesized that shp would also mediate negative feedback regulation of ntcp, the principal hepatic bile acid transporter. Methods: Primary rat hepatocytes or transfected HepG2 and Cos cells were treated with retinoids with or without bile acids, and effects on bile acid transport and ntcp and shp gene expression and promoter activity were determined. Gel shift assays were performed using synthetic fry, rxr, and rar proteins. Results: Bile acid treatment of primary rat hepatocytes prevented retinoid activation of ntcp gene expression and function; this corresponded temporally with shp gene activation. Bile acid-mediated down-regulation occurred via fxr-dependent suppression of the ntcp RXR:RAR response element. Moreover, cotransfected shp directly inhibited retinoid activation of the ntcp promoter. Conclusions: These studies show negative feedback regulation of ntcp by bile acid-activated fxr via induction of shp. This novel regulatory pathway provides a means for coordinated down-regulation of bile acid import and synthesis, thereby protecting the hepatocyte from bile acid-mediated damage in cholestatic conditions.