Down-regulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis.
OBJECTIVE
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.
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
C
C
Gartung
M
M
Ananthanarayanan
M A
MA
Rahman
S
S
Schuele
S
S
Nundy
C J
CJ
Soroka
A
A
Stolz
F J
FJ
Suchy
J L
JL
Boyer
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D001651:Cholestasis, Extrahepatic / Q000378:metabolism* / Q000473:pathology; D003135:Common Bile Duct; D015536:Down-Regulation; D006706:Homeostasis; D008026:Ligation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters; D013656:Taurocholic Acid / Q000378:metabolism; D014018:Tissue Distribution; D014158:Transcription, Genetic
D002352:Carrier Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D011506:Proteins; D012333:RNA, Messenger; D027981:Symporters; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)