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Impact of experimental colitis on hepatobiliary transporter expression and bile duct injury in mice

Authors

  • Jörg Jahnel,

    1. Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
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  • Peter Fickert,

    1. Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
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  • Cord Langner,

    1. Department of Pathology, Medical University Graz, Austria
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  • Christoph Högenauer,

    1. Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
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  • Dagmar Silbert,

    1. Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
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  • Judith Gumhold,

    1. Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
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  • Andrea Fuchsbichler,

    1. Department of Pathology, Medical University Graz, Austria
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  • Michael Trauner

    1. Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
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Correspondence
Michael Trauner, MD, Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria
Tel: +43 316 385 4388
Fax: +43 316 385 7560
e-mail: michael.trauner@meduni-graz.at

Abstract

Background and Aims: The pathogenetic link between ulcerative colitis and sclerosing cholangitis (SC) is unclear. We hypothesized that colitis induces changes in bile composition via inflammation-induced reduction of hepatobiliary transporter gene expression, ultimately resulting in cholestasis and bile duct injury.

Methods: Alterations in transporter expression and bile secretion in acute dextran sulphate sodium (DSS)-induced colitis were compared with lipopolysaccharide (LPS)-treated mice serving as positive control. Whether chronic DSS-colitis elicits cholangitis in genetically predisposed animals was studied in heterozygous multidrug resistance gene 2 knockout mice (Mdr2+/−).

Results: LPS but not DSS-colitis changed major hepatobiliary transporters (Ntcp, Bsep, Mrp2-4, Ostα/β, Abcg5/8, Oatp1–4, Mdr1b and Mdr2), enzymes (Cyp3a11 and Cyp7a1), nuclear receptors (RXRα, FXR, CAR and PXR) and proinflammatory mediators (tumour necrosis factor α and inducible nitric oxide synthase). Formation of toxic bile reflected by an increased bile acid/phospholipid ratio was observed neither in acute nor in chronic colitis, although heterozygous Mdr2+/− mice developed mild portal inflammation after chronic colitis.

Conclusions: In contrast to LPS, DSS-colitis has a minor impact on hepatobiliary gene expression and bile secretion. Therefore, intestinal inflammation-associated changes of hepatobiliary transporter expression do not play a pathogenetic role in SC.

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