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1 Department of Pharmacokinetics & Drug Delivery, University of Groningen, Groningen, Groningen, The Netherlands
2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Groningen, Groningen, Groningen, The Netherlands
3 Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Hospital Groningen, Groningen, Groningen, The Netherlands
* To whom correspondence should be addressed. E-mail: M.G.L.Elferink{at}farm.rug.nl.
Endotoxin-induced cholestasis in rodents is caused by hepatic down-regulation
of transporters, including the basolateral Na+-dependent taurocholate transporter (ntcp)
and the canalicular bile salt export pump (bsep) and multi drug resistance associated
protein 2 (mrp2). Details about the regulation of the human transporter proteins during this
process are lacking. We used precision-cut human and rat liver slices to study the
regulation of transporter expression during LPS-induced cholestasis. We investigated the
effect of LPS on NOx and cytokine production in relation to the expression of iNOS, NTCP,
BSEP and MRP2 both at the level of mRNA with RT-PCR and protein using immuno-fluorescence
microscopy. In liver slices from both species, LPS-induced expression of
iNOS was detected within 1-3 h, and remained increased over 24 h. In rat liver slices, this
was accompanied by a significant decrease of rat ntcp- and mrp2 mRNA levels, while
bsep levels were not affected. These results are in line with previous in vivo studies and
validate our liver slice technique. In LPS-treated human liver slices, NTCP mRNA was
down-regulated and showed an inverse correlation with the amounts of TNF
and Il-1
produced. In contrast, MRP2 and BSEP mRNA levels were not affected under these
conditions. However, after 24 h LPS challenge both proteins were virtually absent in
human liver slices, whereas marker proteins remained detectable. In conclusion, we show
that post-transcriptional mechanisms play a more prominent role in LPS-induced
regulation of human MRP2 and BSEP, compared to the rat transporter proteins.
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