Loss of bile salt export pump (Bsep/Abcb11) aggravates lipopolysaccharide induced hepatic inflammation in mice

Bsep is the main canalicular transporter for biliary bile acid (BA) secretion. Although lack of BSEP causes severe cholestasis in human, Bsep KO mice are protected from acquired cholestasis because of metabolic preconditioning with hydrophilic BA pool. Here we investigate whether a hydrophilic BA pool may counteract development of hepatic inflammation. WT and Bsep KO mice were challenged with LPS to induce hepatic inflammation. Serum biochemistry and liver histology were assessed. Hepatic markers of inflammation were analyzed by qPCR, Western blotting and immunohistochemistry. Bsep KO mice developed more severe LPS-induced liver inflammation than WT mice. LPS treatment increased ALT and AST levels in Bsep KO mice compared to corresponding control group (p ≤0.05), but remained unchanged in WT mice. AST, ALT and AP were elevated 6 fold, 3 fold, 3 fold in LPS treated Bsep KO mice compared to challenged WT mice, respectively (p ≤0.05). NF-kB was significantly higher in LPS treated Bsep KO mice compared to WT mice at mRNA (1.7 fold; p ≤0.05) and protein level (1.8 fold; p = 0.052). Inflammation was reflected by elevated mRNA-expression of Vcam (1.3 fold), Icam (1.7 fold), IL1b (2 fold), Mcp1 (2.5 fold), Tnfa (2.7 fold), IL6 (3.2 fold) and iNos (5 fold) (p ≤0.05). MAC2-staining showed increased immune cell number in livers of Bsep KO compared to WT. Ppara and Nrf2 were significantly reduced upon LPS challenge in Bsep KO mice at RNA level (60%; 40%, respectively; p ≤0.05). Fxra was down-regulated in Bsep KO mice at mRNA level (53%; p ≤0.05). Cyp2b10 was reduced by 53% (p ≤0.05) in Bsep KO LPS treated mice compared to Bsep KO controls and by 40% compared to WT LPS challenged mice. Absence of Bsep aggravates hepatic inflammation upon LPS, potentially by reduction of anti-inflammatory signaling via Fxra, Ppara and Nrf2 as well as reduction of BA detoxification.