Z Gastroenterol 2018; 56(05): e39
DOI: 10.1055/s-0038-1654634
POSTER
Hepatologie
Georg Thieme Verlag KG Stuttgart · New York

Loss of BSEP/ABCB11 protects MDR2/ABCB4 KO mice from cholestatic liver injury by altering bile acid profile and signaling

CD Fuchs
1   Medical University of Vienna, Vienna, Austria
,
G Paumgartner
1   Medical University of Vienna, Vienna, Austria
,
S Wolfrum
2   Laboratorium für Organische Chemie, ETH Zürich, Zürich, Switzerland
,
A Wahlström
3   Department of Molecular and Clinical Medicine, Gothenburg, Sweden
,
M Stahlman
3   Department of Molecular and Clinical Medicine, Gothenburg, Sweden
,
T Stojakovic
4   Medical University of Graz, Graz, Austria
,
C Wolfrum
5   Laboratorium für Organische Chemie, ETH Zürich, Switzerland
,
H Marschall
3   Department of Molecular and Clinical Medicine, Gothenburg, Sweden
,
M Trauner
1   Medical University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Publication Date:
09 May 2018 (online)

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Background and Aim:

Cholestasis is characterized as intrahepatic accumulation of potentially cytotoxic bile acids (BAs) which subsequently leads to cholestatic liver injury. Bile salt export pump (Bsep/Abcb11) is the main canalicular BA transporter and therefore the rate limiting step for hepatobiliary BA secretion. In this study we aim to investigate the role of Bsep/Abcb11 in development of liver injury in a mouse model of sclerosing cholangitis – the (Mdr2/Abcb4) KO mouse.

Methods:

Mdr2/Bsep (Abcb4/Abcb11) double knockout (DKO) mice were generated. Gene expression profile, serum biochemistry, liver histology, immunohistochemistry (IHC) and serum BA composition were assessed. Mdr2/Abcb4 KO mice as well as WT mice subjected to bile duct ligation (BDL) were fed with a tetrahydroxylated bile acid (THBA). Serum biochemistry, histology, IHC and geneexpression profiling were assessed.

Results:

In contrast to Mdr2/Abcb4 KO mice, DKO mice did not show liver injury. Gene-expression-profile of inflammatory markers remained unchanged (compared to WT Ctrls) in DKO mice, while in Mdr2 KO mice these markers were dramatically increased. IHC showed same amount of F4/80 positive cells in DKO versus WT mice. Fibrosis markers were increased in Mdr2 KO mice but remained unchanged in DKO mice. Cyp3a11 and Cyp2b10 expression, (two enzymes involved in BA hydroxylation/detoxification) is increased in DKO mice 5fold and 100fold, respectively, while in Mdr2 KO mice both genes are unchanged. In line, 67% of BAs found in serum of DKO mice are polyhydroxylated, with tetrahydroxylated BAs being the most prominent one, while in Mdr2 KO mice these BA species are completely absent. THBA feeding improved inflammation and fibrosis in Mdr2/Abcb4 KO. Also in WT mice subjected to BDL THBA feeding improved inflammation, reflected by improved genexpression profile of inflammatory markers.

Conclusion:

PHBA may be a new potential treatment strategy for cholestatic liver diseases.