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Articles in PresS, published online ahead of print September 21, 2001
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00215.2001
Submitted on May 22, 2001
Accepted on September 4, 2001
1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Karl-Franzens University, Graz, Austria
2 Department of Pathology, Karl-Franzens University, Graz, Austria
* To whom correspondence should be addressed. E-mail: michael.trauner{at}kfunigraz.ac.at.
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 (i) down-regulation of Ntcp in obstructive cholestasis is a consequence of bile acid retention and (ii) 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 hours (h) and compared to 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 down-regulation 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 down-regulation of Ntcp in CBDL mice. These findings support the concept, that down-regulation of Ntcp in cholestasis limits intracytoplasmatic accumulation of potentially toxic bile acids.
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