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Fickert, P; Trauner, M; Fuchsbichler, A; Stumptner, C; Zatloukal, K; Denk, H.
Bile acid-induced Mallory body formation in drug-primed mouse liver.
Am J Pathol. 2002; 161(6):2019-2026 [OPEN ACCESS]
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Authors Med Uni Graz:
Denk Helmut
Fickert Peter
Stumptner Cornelia
Trauner Michael
Zatloukal Kurt
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Number of Figures: 4
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Abstract:
Chronic cholestasis is associated with retention of bile acids and profound cytoskeletal alterations in hepatocytes including Mallory body (MB) formation. The mechanisms responsible for MB formation in cholestatic liver diseases are unclear. The aim of our study was to determine the relevance of cholestasis and bile acids for MB formation. For this purpose mice received a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet for 2.5 months to induce MB formation. After recovery from DDC intoxication for 4 weeks followed by disappearance of MBs, these drug-primed mice were subjected to DDC refeeding, common bile duct ligation (CBDL), and feeding of a cholic acid (CA)-supplemented diet for 7 days, respectively. Cytokeratin (CK) 8 and CK 18 expression was studied by competitive reverse transcriptase-polymerase chain reaction and Western blot analysis. Cytoskeletal alterations of hepatocytes and MB formation were monitored by immunofluorescence microscopy and immunohistochemistry using CK-, ubiquitin-, and MB-specific antibodies. Like DDC refeeding, both CBDL and CA feeding of drug-primed mice significantly increased CK 8 and CK 18 mRNA and protein levels (with excess of CK 8) and resulted in ubiquitination and abnormal phosphorylation of CKs. Furthermore, CBDL and CA feeding resulted in rapid neoformation of MBs in drug-primed mice. It is concluded that MB formation in cholestatic liver diseases may be triggered by the action of potentially toxic bile acids.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Bile Acids and Salts - metabolism
Bile Ducts - surgery
Cholestasis - metabolism Cholestasis - pathology
Cholic Acid - administration and dosage Cholic Acid - metabolism
Dicarbethoxydihydrocollidine - administration and dosage Dicarbethoxydihydrocollidine - chemistry Dicarbethoxydihydrocollidine - pharmacology
Diet -
Hepatocytes - drug effects Hepatocytes - metabolism Hepatocytes - ultrastructure
Humans -
Inclusion Bodies - metabolism Inclusion Bodies - ultrastructure
Keratins - genetics Keratins - metabolism
Ligation -
Liver - drug effects Liver - enzymology Liver - ultrastructure
Male -
Mice -
Phosphorylation -
Ubiquitin - metabolism

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