[HTML][HTML] Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis
C Gartung, M Ananthanarayanan, MA Rahman… - Gastroenterology, 1996 - Elsevier
C Gartung, M Ananthanarayanan, MA Rahman, S Schuele, S Nundy, CJ Soroka, A Stolz…
Gastroenterology, 1996•ElsevierBACKGROUND & 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 …
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 …
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. (Gastroenterology 1996 Jan;110(1):199-209)
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