Impact of experimental colitis on hepatobiliary transporter expression and bile duct injury in mice.
OBJECTIVE
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, Ostalpha/beta, Abcg5/8, Oatp1-4, Mdr1b and Mdr2), enzymes (Cyp3a11 and Cyp7a1), nuclear receptors (RXRalpha, FXR, CAR and PXR) and proinflammatory mediators (tumour necrosis factor alpha 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.
Jahnel
Jörg
J
Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Auenbruggerplatz 15, Graz, Austria.
Fickert
Peter
P
Langner
Cord
C
Högenauer
Christoph
C
Silbert
Dagmar
D
Gumhold
Judith
J
Fuchsbichler
Andrea
A
Trauner
Michael
M
D000818:Animals; D018988:Bacterial Translocation; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001647:Bile Acids and Salts / Q000032:analysis; D001652:Bile Ducts / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D015209:Cholangitis, Sclerosing / Q000209:etiology*; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010743:Phospholipids / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D010743:Phospholipids; D012333:RNA, Messenger; D016264:Dextran Sulfate