DOWN-REGULATION OF EXPRESSION AND FUNCTION OF THE RAT-LIVER NA+ BILE ACID COTRANSPORTER IN EXTRAHEPATIC CHOLESTASIS/

Background & Aims: The molecular regulation of hepatic bile acid trans porters during cholestasis is largely unknown. Cloning of complementar y DNAs for the sinusoidal sodium-dependent taurocholate cotransporting polypeptide (ntcp), the cytosolic bile acid-binding protein 3 alpha-h ydroxysteroid dehydrogenase (3 alpha-HSD), and a putative canalicular bile acid transporter Ca2+, Mg2+-ecto-adenosine triphosphatase, now fa cilitates 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, N at-dependent taurocholate uptake (V-max) declined by 70%, The levels o f ntcp protein were reduced by more than 90%, and 3 alpha-HSD levels d ecreased 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 decreas ed 1 day after CBDL only for ntcp, Conclusions: Extrahepatic cholestas is results in rapid down-regulation of Na+-dependent taurocholate upta ke, ntcp transcription, and posttranscriptional regulation of both ntc p and 3 alpha-HSD mRNA, This selective decline of ntcp may represent a protective feedback mechanism in cholestasis to diminish uptake of po tentially hepatotoxic bile acids.