Page 183 - OSLO 2017 - ebook

P07.02

Colesevelam attenuates cholestatic liver and bile duct
injury in Mdr2-/- mice by modulating composition,
signaling and excretion of fecal bile acids

Claudia D. Fuchs , Gustav Paumgartner , Emina Halilbasic , Annika Wahlström ,
1
2
1
1
1
2
3
4
Nadja Leditznig , Andrea Thüringer , Marcus Stahlman , Tatjana Stojakovic ,
Karl Kashofer , Hanns-Ulrich Marschall , Michael Trauner * 1
3
2
2
1 Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria, Molecular
and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden, Institute of Pathology,
3
4 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz,
Graz, Austria
Corresponding author’s email: claudia.fuchs@meduniwien.ac.at
Introduction: Following their biliary excretion, bile acids (BAs) are reabsorbed from the
intestine and recirculate back to the liver. Interruption of the enterohepatic circulation
of BAs may protect against BA-mediated cholestatic liver and bile duct injury. BA
sequestrants are used for symptomatic treatment of cholestatic pruritus but their impact
on the underlying cholestasis is still unclear. ePOSTER ABSTRACTS PRESENTATIONS
Aims: We aimed to explore the therapeutic effects of the BA sequestrant Colesevelam
(CS) and potential mechanistic differences to selective uptake (ASBT) inhibition in
improving cholestasis, inflammation and biliary fibrosis.
Material and Methods: Mdr2-/- mice (as mouse model of cholestasis and sclerosing
cholangitis) received CS (2% w/w diet) for 8 weeks. Gene expression profiles in liver
and intestine were assessed via RT-PCR. GLP-1 levels in portal blood were measured by
ELISA and immuohistochemistry was performed from colon. αSMA and OH-proline
were assessed at protein levels. 16s rRNA microbiota analysis as also performed.

Results: CS improved serum liver enzymes (AST, ALT, AP) and BA levels, hepatic
expression of pro-inflammatory (Tnf-α by -90%; Vcam1 -95%; Mcp-1 -90%) and pro-
fibrogenic (Col1a1 by -90%; Col1a2 -90%) genes as well as bile duct proliferation (CK19
-95%). At protein levels CS reduced OH-proline and αSMA (p ≤0.001). Total fecal BA
output increased 6-fold by CS treatment consisting of more than 50% of secondary BAs
such as (tauro)LCA and (tauro)DCA (TGR5 ligands). Serum GLP-1 levels and mRNA
expression of Proglucagon were increased in CS-fed mice 3.5-fold and 5-fold, respectively,

EASL Monothematic Conference • Oslo, Norway • 9-11 June 2017 183