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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Zollner, G; Wagner, M; Fickert, P; Geier, A; Fuchsbichler, A; Silbert, D; Gumhold, J; Zatloukal, K; Kaser, A; Tilg, H; Denk, H; Trauner, M.
Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver.
Am J Physiol Gastrointest Liver Physiol. 2005; 289(5):G798-G805 Doi: 10.1152/ajpgi.00319.2004 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Trauner Michael
Zollner Gernot
Co-Autor*innen der Med Uni Graz
Denk Helmut
Fickert Peter
Silbert-Wagner Dagmar
Sommer Judith
Wagner Martin
Zatloukal Kurt
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Abstract:
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.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Chemokines - genetics
Cholestasis - genetics Cholestasis - metabolism
Cholic Acid - pharmacology
Cytokines - genetics
Down-Regulation - drug effects
Hepatocytes - metabolism
Lipopolysaccharides - pharmacology
Liver - metabolism Liver - pathology
Membrane Transport Proteins - genetics
Mice -
Mice, Inbred C57BL -
Mice, Knockout -
Organic Anion Transporters, Sodium-Dependent -
RNA, Messenger - genetics RNA, Messenger - metabolism
Receptors, Cytoplasmic and Nuclear - deficiency Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism
Symporters -
Transcription Factors - metabolism

Find related publications in this database (Keywords)
bile acids
cytokines
bile duct obstruction
orphan nuclear receptors
cholestasis
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