title: Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice.
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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Karl-Franzens University, Graz, A-8036 Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Zollner
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Dagmar
authors.initials: D
authors.lastname: Silbert
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuchsbichler
authors.forename: Conny
authors.initials: C
authors.lastname: Stumptner
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001652:Bile Ducts / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D001651:Cholestasis, Extrahepatic / Q000378:metabolism / Q000503:physiopathology*; D019826:Cholic Acid / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D027981:Symporters
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; C099713:nuclear receptor subfamily 0, group B, member 2; C071908:sodium-bile acid cotransporter; D019826:Cholic Acid