Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug...

Hepatic dysfunction in sepsis is characterized by hyperbilirubinemia and intrahepatic cholestasis. We hypothesize that sepsis causes decreased hepatic transcription of the bile acid transporter sodium taurocholate cotransporter (Ntcp) and the organic anion transporter multidrug resistance-associated protein (Mrp2) and that interleukin (IL)-6 is important in the down-regulation of Ntcp and Mrp2 expression. Male Sprague-Dawley rats underwent induction of mild, nonlethal sepsis by cecal ligation and single puncture (CLP) or fulminant sepsis by cecal ligation and double puncture (2CLP). Hepatic transcription of Ntcp and Mrp2 rapidly decreased after CLP or 2CLP. Seventy-two hours later, transcription was 60% of baseline in CLP and 14% of baseline in 2CLP. Serum bilirubin was elevated from 24 h onward and cholestasis was 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 cultured hepatocytes and in normal rats given 1 mg/kg intravenous IL-6. We conclude that 1) Ntcp and Mrp2 transcription is down-regulated transiently after CLP and persistently after 2CLP; 2) 2CLP results in hyperbilirubinemia and cholestasis, in part due to persistently decreased transcription of Ntcp and Mrp2; and 3) altered Ntcp and Mrp2 transcription is mediated in part by IL-6.