Gartung C, Ananthanarayanan M, Rahman M A, Schuele S, Nundy S, Soroka C J, Stolz A, Suchy F J, Boyer J L
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Gastroenterology. 1996 Jan;110(1):199-209. doi: 10.1053/gast.1996.v110.pm8536857.
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+, Mg(2+)-ecto-adenosine triphosphatase, now facilitates such studies.
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.
After CBDL, Na(+)-dependent taurocholate uptake (Vmax) 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.
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.
胆汁淤积时肝脏胆汁酸转运体的分子调控机制大多尚不明确。窦状隙钠依赖性牛磺胆酸盐共转运多肽（ntcp）、胞质胆汁酸结合蛋白3α-羟基类固醇脱氢酶（3α-HSD）以及一种假定的胆小管胆汁酸转运体Ca2+、Mg(2+)-外向型三磷酸腺苷酶互补DNA的克隆，为这类研究提供了便利。
在胆总管结扎（CBDL）1至7天后，评估大鼠肝脏中的蛋白质质量、稳态信使核糖核酸（mRNA）水平及基因转录情况，并测定分离肝细胞中牛磺胆酸盐的摄取量。
CBDL后，钠依赖性牛磺胆酸盐摄取（Vmax）下降了70%。ntcp蛋白水平降低超过90%，3α-HSD水平在7天时下降了66%。外向型三磷酸腺苷酶的表达及胆小管定位未发生改变。CBDL后1天，ntcp和3α-HSD的mRNA水平均下降约60%，直至7天保持不变。仅ntcp的转录活性在CBDL后1天降低。
肝外胆汁淤积导致钠依赖性牛磺胆酸盐摄取、ntcp转录以及ntcp和3α-HSD mRNA的转录后调控迅速下调。ntcp的这种选择性下降可能代表胆汁淤积时一种保护性反馈机制，以减少对潜在肝毒性胆汁酸的摄取。
