Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver.
Expression of the main hepatic bile acid uptake system, the Na+-taurocholate cotransporter (Ntcp), is downregulated during cholestasis. Bile acid-induced, farnesoid X receptor (FXR)-mediated induction of the nuclear repressor short heterodimer partner (SHP) has been proposed as a key mechanism reducing Ntcp expression. However, the role of FXR and SHP or other nuclear receptors and hepatocyte-enriched transcription factors in mediating Ntcp repression in obstructive cholestasis is unclear. FXR knockout (FXR-/-) and wild-type (FXR+/+) mice were subjected to common bile duct ligation (CBDL). Cholic acid (CA)-fed and LPS-treated FXR-/- and FXR+/+ mice were studied for comparison. mRNA levels of Ntcp and SHP and nuclear protein levels of hepatocyte nuclear factor (HNF)-1alpha, HNF-3beta, HNF-4alpha, retinoid X receptor (RXR)-alpha, and retinoic acid receptor (RAR)-alpha and their DNA binding were assessed. Hepatic cytokine mRNA levels were also measured. CBDL and CA led to Ntcp repression in FXR+/+, but not FXR-/-, mice, whereas LPS reduced Ntcp expression in both genotypes. CBDL and LPS but not CA induced cytokine expression and reduced levels of HNF-1alpha, HNF-3beta, HNF-4alpha, RXRalpha, and RARalpha to similar extents in FXR+/+ and FXR-/-. DNA binding of these transactivators was unaffected by CA in FXR+/+ mice but was markedly reduced in FXR-/- mice. In conclusion, Ntcp repression by CBDL and CA is mediated by accumulating bile acids via FXR and does not depend on cytokines, whereas Ntcp repression by LPS is independent of FXR. Reduced levels of HNF-1alpha, RXRalpha, and RARalpha in CBDL FXR-/- mice and reduced DNA binding in CA-fed FXR-/- mice, despite unchanged Ntcp levels, indicate that these factors may have a minor role in regulation of mouse Ntcp during cholestasis.
Zollner
Gernot
G
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria.
Wagner
Martin
M
Fickert
Peter
P
Geier
Andreas
A
Fuchsbichler
Andrea
A
Silbert
Dagmar
D
Gumhold
Judith
J
Zatloukal
Kurt
K
Kaser
Arthur
A
Tilg
Herbert
H
Denk
Helmut
H
Trauner
Michael
M
D000818:Animals; D018925:Chemokines / Q000235:genetics; D002779:Cholestasis / Q000235:genetics* / Q000378:metabolism; D019826:Cholic Acid / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D027981:Symporters; D014157:Transcription Factors / Q000378:metabolism*
D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D014157:Transcription Factors; C071908:sodium-bile acid cotransporter; D019826:Cholic Acid