AI Article Synopsis
- The study investigates how chronic exposure to griseofulvin (GF) changes liver keratin levels and leads to the formation of Mallory bodies, characteristic of alcoholic hepatitis.
- The researchers found that while there was an increase in mRNA for liver keratins A (8) and D (18) in GF-treated livers, the actual keratin intermediate filaments (IFs) were diminished, suggesting a disconnect between mRNA levels and protein presence.
- The findings imply that posttranslational modifications may disrupt keratin IF assembly, as changes in mRNA levels precede observable alterations in the IF network.
Article Abstract
Background: Alterations of the hepatocytic intermediate filament (IF) cytoskeleton, i.e., derangement and diminution of the keratin network and appearance of cytoplasmic aggregates of keratin-containing material, termed Mallory bodies, are characteristic features of human alcoholic hepatitis. Mallory bodies can be experimentally produced in mouse liver by chronic griseofulvin (GF) administration. GF intoxication of mice is, therefore, a suitable model to study the mechanisms of Mallory body formation and related cytoskeletal changes.
Experimental Design: To investigate the correlation between morphologic alterations of the keratin cytoskeletal network and the mRNA levels for liver keratins A (8) and D (18) in this pathologic situation immunohistochemical studies and northern blot analyses were performed. The amount of mRNA for both keratins was also analyzed by nuclease S1 protection assay.
Results: In GF-treated livers (4 months of treatment) an increase of mRNA for both liver keratins was found. This increase of mRNA was unexpected under these conditions, since in longterm GF-fed animals, the amount of keratin IFs was reduced as revealed by immunofluorescence and electron microscopy and by biochemical analysis of keratin proteins. In livers treated for 2 months with GF the IF meshwork seemed to be still intact, but the increase of RNA was already detectable indicating that alterations of keratin mRNA precede detectable morphologic alterations. When using this mRNA for in vitro translation experiments, strong keratin polypeptide spots could be detected by autoradiography of 2-dimensional gels.
Conclusions: These results strongly suggest that in vivo under the conditions of GF intoxication posttranslational modifications, like phosphorylation, proteolysis and covalent cross-linking, could influence IF homeostasis and interfere with IF assembly. Increase of mRNA for liver keratins despite IF protein reduction might be due to negative feedback regulation.
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