title: Cytokeratins as targets for bile acid-induced toxicity.
abstract: Cholestasis is associated with retention of potentially toxic bile acids and profound cytoskeletal alterations of hepatocytes. Given the well-established cytoprotective role of hepatocyte keratins this study aimed to determine the effects of cholestasis on the cytokeratin (CK) intermediate filament network in mouse liver. Mice were subjected to common bile duct ligation or sham operation. Mice were also fed a cholic acid or ursodeoxycholic acid (UDCA)-supplemented diet (0.1%, 0.5%, and 1%) or control diet for 7 days. CK 8 and CK 18 expression was studied by competitive reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot analysis, and immunofluorescence microscopy. Common bile duct ligation and cholic acid feeding significantly stimulated CK 8 and CK 18 mRNA and protein levels compared to controls, whereas UDCA had no effect. CK overexpression was accompanied by pronounced phosphorylation. Our results show that potentially toxic bile acids induce hepatocytic CK 8 and CK 18 expression and phosphorylation whereas nontoxic UDCA has no effect on CKs. Thus, increased hepatocellular CK expression and phosphorylation in cholestasis may be caused by retention of toxic bile acids and reflect a hepatocellular stress response with potential beneficial effects.
authors.affiliation: Department of Medicine, University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuchsbichler
authors.forename: Conny
authors.initials: C
authors.lastname: Stumptner
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000633:toxicity*; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000503:physiopathology*; D003599:Cytoskeleton / Q000378:metabolism; D004032:Diet; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007382:Intermediate Filaments / Q000378:metabolism; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice
chemical_list: D001647:Bile Acids and Salts; D007633:Keratins