Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Zollner, G; Fickert, P; Silbert, D; Fuchsbichler, A; Stumptner, C; Zatloukal, K; Denk, H; Trauner, M.
Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice.
Am J Physiol Gastrointest Liver Physiol. 2002; 282(1):G184-G191
Doi: 10.1152/ajpgi.00215.2001
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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
- Stumptner Cornelia
- Zatloukal Kurt
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- Abstract:
- Cholestasis is associated with retention of bile acids and reduced expression of the Na(+)/taurocholate cotransporter (Ntcp), the major hepatocellular bile acid uptake system. This study aimed to determine whether downregulation of Ntcp in obstructive cholestasis 1) is a consequence of bile acid retention and 2) is mediated by induction of the transcriptional repressor short heterodimer partner 1 (SHP-1). To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls. Serum bile acid levels were determined by radioimmunoassay. SHP-1 and Ntcp steady-state mRNA expression were assessed by Northern blotting. In addition, Ntcp protein expression was studied by Western blotting and immunofluorescence microscopy. Increased SHP-1 mRNA expression paralleled elevations of serum bile acid levels and was followed by downregulation of Ntcp mRNA and protein expression in CBDL mice. Maximal SHP-1 mRNA expression reached a plateau phase after 6-h CBDL (12-fold; P < 0.001) and preceded the nadir of Ntcp mRNA levels (12%, P < 0.001) by 6 h. In conclusion, bile acid-induced expression of SHP-1 may, at least in part, mediate downregulation of Ntcp in CBDL mice. These findings support the concept that downregulation of Ntcp in cholestasis limits intracytoplasmatic accumulation of potentially toxic bile acids.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Bile Acids and Salts - blood
- Bile Ducts - metabolism Bile Ducts - physiopathology
- Blotting, Western -
- Carrier Proteins - analysis Carrier Proteins - genetics Carrier Proteins - metabolism
- Cholestasis, Extrahepatic - metabolism Cholestasis, Extrahepatic - physiopathology
- Cholic Acid - pharmacology
- Cytokines - physiology
- Down-Regulation - physiology
- Fluorescent Antibody Technique -
- Gene Expression - drug effects Gene Expression - physiology
- Ligation -
- Lipopolysaccharides - pharmacology
- Male -
- Membrane Transport Proteins -
- Mice -
- Mice, Inbred Strains -
- Organic Anion Transporters, Sodium-Dependent -
- RNA, Messenger - analysis
- Receptors, Cytoplasmic and Nuclear - genetics
- Symporters -
- Find related publications in this database (Keywords)
- cholestasis
- bile acids
- proinflammatory cytokines
- transport
- orphan nuclear receptors
- transcription factors