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LIVER AND BILIARY TRACT
1Department of Pharmacokinetics and Drug Delivery, University of Groningen, 9713 AV Groningen; 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Groningen, 9713 GZ Groningen; and 3Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Hospital Groningen, 9713 GZ Groningen, The Netherlands
Submitted 11 February 2004 ; accepted in final form 4 June 2004
Endotoxin-induced cholestasis in rodents is caused by hepatic downregulation of transporters, including the basolateral Na+-dependent taurocholate transporter (ntcp) and the canalicular bile salt export pump (bsep) and multidrug 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 nitrate/nitrite and cytokine production in relation to the expression of inducible nitric oxide synthase, NTCP, BSEP, and MRP2 both at the level of mRNA with RT-PCR and protein using immunofluorescence microscopy. In liver slices from both species, LPS-induced expression of inducible nitric oxide synthase 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, whereas 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 downregulated 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 posttranscriptional mechanisms play a more prominent role in LPS-induced regulation of human MRP2 and BSEP compared with the rat transporter proteins.
human liver slices; endotoxin-induced cholestasis; transporter expression; cytokines; immunofluorescence microscopy
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