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首页> 外文期刊>American Journal of Physiology >Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice.
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Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice.

机译：短异源二聚体伴侣1的诱导在胆管结扎小鼠中Ntcp的下调之前。

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摘要

Cholestasis is associated with retention of bile acids and reduced expression of the Na(+)/taurocholate cotransporter (Ntcp), the major hepatocellular bile acid uptake system. This study aimed to determine whether downregulation of Ntcp in obstructive cholestasis 1) is a consequence of bile acid retention and 2) is mediated by induction of the transcriptional repressor short heterodimer partner 1 (SHP-1). To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls. Serum bile acid levels were determined by radioimmunoassay. SHP-1 and Ntcp steady-state mRNA expression were assessed by Northern blotting. In addition, Ntcp protein expression was studied by Western blotting and immunofluorescence microscopy. Increased SHP-1 mRNA expression paralleled elevations of serum bile acid levels and was followed by downregulation of Ntcp mRNA and protein expression in CBDL mice. Maximal SHP-1 mRNA expression reached a plateau phase after 6-h CBDL (12-fold; P < 0.001) and preceded the nadir of Ntcp mRNA levels (12%, P < 0.001) by 6 h. In conclusion, bile acid-induced expression of SHP-1 may, at least in part, mediate downregulation of Ntcp in CBDL mice. These findings support the concept that downregulation of Ntcp in cholestasis limits intracytoplasmatic accumulation of potentially toxic bile acids.
机译：胆汁淤积与胆汁酸的保留和Na（+）/牛磺胆酸盐共转运蛋白（Ntcp）（主要的肝细胞胆汁酸摄取系统）的表达降低有关。这项研究旨在确定在胆汁淤积性胆汁淤积症中Ntcp的下调是否是胆汁酸retention留的结果，而2）是由转录阻抑物短异二聚体伴侣1（SHP-1）的诱导介导的。为了研究血清胆汁酸水平以及SHP-1和Ntcp稳态mRNA水平变化的时程，对小鼠进行了3、6、12、24、72和72的胆总管结扎（CBDL）。 168小时，与假手术对照组比较。通过放射免疫测定法测定血清胆汁酸水平。通过Northern印迹评估SHP-1和Ntcp稳态mRNA表达。另外，通过蛋白质印迹和免疫荧光显微镜研究了Ntcp蛋白的表达。 SHP-1 mRNA表达增加与血清胆汁酸水平升高平行，随后CBDL小鼠中Ntcp mRNA和蛋白表达下调。 SHP-1 mRNA的最大表达在CBDL 6小时后达到平稳期（12倍; P <0.001），并在Ntcp mRNA水平最低点（12％，P <0.001）之前6 h。总之，胆汁酸诱导的SHP-1表达可能至少部分介导了CBDL小鼠Ntcp的下调。这些发现支持了胆汁淤积中Ntcp的下调限制了潜在毒性胆汁酸的胞浆内积累的概念。

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