Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats

Hepatic dysfunction in sepsis is characterized by hyperbilirubinemia and in trahepatic cholestasis. We hypothesize that sepsis causes decreased hepatic transcription of the bile acid transporter sodium taurocholate cotransport er (Ntcp) and the organic anion transporter multidrug resistance-associated protein (Mrp2) and that interleukin (IL)-6 is important in the down-regula tion of Ntcp and Mrp2 expression. Male Sprague-Dawley rats underwent induct ion of mild, nonlethal sepsis by cecal ligation and single puncture (CLP) o r fulminant sepsis by cecal ligation and double puncture (2CLP), Hepatic tr anscription of Ntcp and Mrp2 rapidly decreased after CLP or 2CLP. Seventy-t wo hours later, transcription was 60% of baseline in CLP and 14% of baselin e in 2CLP. Serum bilirubin was elevated from 24 h onward and cholestasis wa s observed on fixed liver specimens at 24, 48, and 72 h after 2CLP but not after CLP. Steady-state Ntcp and Mrp2 mRNA was decreased in IL-6-treated cu ltured hepatocytes and in normal rats given 1 mg/kg intravenous IL-6. We co nclude that 1) Ntcp and Mrp2 transcription is down-regulated transiently af ter CLP and persistently after 2CLP; 2) 2CLP results in hyperbilirubinemia and cholestasis, in part due to persistently decreased transcription of Ntc p and Mrp2; and 3) altered Ntcp and Mrp2 transcription is mediated in part by IL-6.