Absence of BSEP/ABCB11 protects from cholestatic liver and bile duct injury in a mouse model of sclerosing Cholangitis

CD Fuchs; G Paumgartner; A Wahlström; T Stojakovic; H Marschall; M Trauner

doi:10.1055/s-0035-1551778

Zeitschrift für Gastroenterologie, Table of Contents

Absence of BSEP/ABCB11 protects from cholestatic liver and bile duct injury in a mouse model of sclerosing Cholangitis

CD Fuchs ¹, G Paumgartner ¹, A Wahlström ², T Stojakovic ³, H Marschall ², M Trauner ¹

¹Internal Medicine III, Medical University of Vienna, Vienna, Austria
²Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
³Medical University of Graz, Graz, Austria

Abstract

Cholestasis leads to liver injury reflected by disruption of hepatocellular integrity, inflammation and fibrosis. Bile salt export pump (BSEP/ABCB11) is the main canalicular BA transporter and therefore rate limiting step for hepatobiliary BA secretion. Here we investigate the role of ABCB11 in development of cholestatic liver and bile duct injury in a model of sclerosing cholangitis. WT and ABCB11KO mice were subjected to common bile duct ligation (CBDL) and DDC feeding as models for acute and chronic cholestasis, respectively. RNA profiling was performed by RT-PCR. BA transporter expression was assessed at protein level. Serum biochemistry, hepatic hydroxyproline (HP) levels, BA composition as well as liver histology were assessed. ABCB11 KO mice where protected from cholestatic liver injury after CBDL or DDC feeding, reflected by unchanged serum levels of ALT, AST, AP, total cholesterol and BA. ABCB11 KO mice where protected from inflammation and fibrosis while WT mice display significant up-regulation of both inflammatory (F4/80 4-fold and Mcp1 60-fold) and fibrotic (Col1a1 2-fold, Col1a2 2,5-fold, HP levels 2-fold) markers. Polyhydroxylated BAs (PHBA) were increased 4-fold in ABCB11KO CBDL mice compared to WT CBDL mice (p < 0,01). mRNA expression of Cyp2b10, downstream target of CAR, a nuclear receptor regulating BA detoxification, was increased (10-fold) in ABCB11KO mice under cholestatic conditions. Protein levels of BA transporter such as NTCP, OATP and MRP2 was reduced in WT and increased in ABCB11KO mice under cholestatic conditions. MRP3and MRP4 protein levels were increased in WT CBDL mice and not changed in ABCB11 KO mice. Notably, the phosphorylated form of STAT3 – essential for the differentiation of pro-inflammatory TH17 cells – was exclusively found in WT BDL mice.

Changes in BA metabolism favouring detoxification and efflux of potentially toxic BAs protects ABCB11 KOmice from development of acute and chronic cholestatic liver injury. Therefore PHBAs may open a new therapeutic avenue against cholestasis and subsequent progression toward fibrosis in cholangiopathies such as PBC and PSC.