Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis

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.

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, 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.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / genetics
  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cholestasis, Extrahepatic / metabolism*
  • Cholestasis, Extrahepatic / pathology
  • Common Bile Duct
  • Down-Regulation
  • Homeostasis
  • Ligation
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Organic Anion Transporters, Sodium-Dependent*
  • Proteins / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Symporters*
  • Taurocholic Acid / metabolism
  • Tissue Distribution
  • Transcription, Genetic


  • Carrier Proteins
  • Organic Anion Transporters, Sodium-Dependent
  • Proteins
  • RNA, Messenger
  • Symporters
  • sodium-bile acid cotransporter
  • Taurocholic Acid
  • 3-Hydroxysteroid Dehydrogenases
  • 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)