Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis
Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis
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DOI：
10.1053/gast.1996.v110.pm8536857
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发表时间：
1996-01-01
期刊：
影响因子：
29.4
通讯作者：
Boyer, JL
中科院分区：
文献类型：
--
作者：
Gartung, C;Ananthanarayanan, M;Boyer, JL
背景与目的：胆汁淤积时肝胆汁酸转运蛋白的分子调控机制尚不清楚。窦状钠依赖性牛磺胆酸盐共转运多肽（ntcp）、胞质胆汁酸结合蛋白3 α-羟基类固醇脱氢酶的互补DNA的克隆（3 α-HSD）和推定的小管胆汁酸转运蛋白Ca 2+，Mg 2 +-外-腺苷三磷酸酶，现在促进了此类研究。胆总管结扎（CBDL）后1-7天，并在分离的肝细胞中测定牛磺胆酸盐摄取。CBDL后7天，Nat依赖性牛磺胆酸摄取（V-max）下降70%，ntcp蛋白水平下降90%以上，3 α-HSD水平下降66%，外腺苷三磷酸酶的表达和小管定位保持不变，NTCP和3 α-HSD的mRNA水平在CBDL后1天降低约60%，并保持不变，直至7天。结论：肝外胆汁淤积导致Na+依赖的牛磺胆酸摄取、ntcp转录以及ntcp和3 α-HSD mRNA转录后调节的快速下调，ntcp的选择性下降可能是胆汁淤积的一种保护性反馈机制，以减少潜在肝毒性胆汁酸的摄取。
Background & Aims: The molecular regulation of hepatic bile acid transporters during cholestasis is largely unknown. Cloning of complementary DNAs for the sinusoidal sodium-dependent taurocholate cotransporting polypeptide (ntcp), the cytosolic bile acid-binding protein 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), and a putative canalicular bile acid transporter Ca2+, Mg2+-ecto-adenosine triphosphatase, now facilitates such studies,Methods: Protein mass, steady-state messenger RNA (mRNA) levels, and gene transcription were assessed in rat livers after common bile duct ligation (CBDL) from 1-7 days, and taurocholate uptake was determined in isolated hepatocytes.Results: After CBDL, Nat-dependent taurocholate uptake (V-max) declined by 70%, The levels of ntcp protein were reduced by more than 90%, and 3 alpha-HSD levels decreased by 66% by 7 days, Expression and canalicular localization of the ecto-adenosine triphosphatase remained unchanged, mRNA levels for both ntcp and 3 alpha-HSD diminished by about 60% 1 day after CBDL and remained unchanged up to 7 days. Transcriptional activity was decreased 1 day after CBDL only for ntcp,Conclusions: Extrahepatic cholestasis results in rapid down-regulation of Na+-dependent taurocholate uptake, ntcp transcription, and posttranscriptional regulation of both ntcp and 3 alpha-HSD mRNA, This selective decline of ntcp may represent a protective feedback mechanism in cholestasis to diminish uptake of potentially hepatotoxic bile acids.