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Protein phosphatase inhibition in normal and keratin 8/18 assembly–incompetent mouse strains supports a functional role of keratin intermediate filaments in preserving hepatocyte integrity
Author(s) -
Toivola Diana M.,
Omary M. Bishr,
Ku Namon,
Peltola Olli,
Baribault Hélène,
Eriksson John E.
Publication year - 1998
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510280117
Subject(s) - intermediate filament , keratin , microfilament , keratin 8 , phosphatase , biology , vacuolization , phosphorylation , microbiology and biotechnology , alkaline phosphatase , intermediate filament protein , in vivo , cytoskeleton , biochemistry , endocrinology , cell , enzyme , genetics
The function and regulation of keratin 8 (K8) and 18 (K18), intermediate filament (IF) proteins of the liver, are not fully understood. We employed the liver damage induced by microcystin‐LR (MC‐LR), a liver‐specific inhibitor of type‐1 and type‐2A protein phosphatases, in normal and in keratin assembly–incompetent mouse strains as a model to elucidate the roles of IF phosphorylation in situ . The mouse strains used were wild‐type (wt) mice and mice with abnormal filament assembly, caused by a targeted null mutation of the K8 gene or caused by expression of a point‐mutated dominant negative human K18. In vivo 32 P‐labeled wt mice, subsequently injected with a lethal dose of MC‐LR, showed hyperphosphorylation, disassembly, and reorganization of K8/K18, in particular K18, indicating high phosphate turnover on liver keratins in situ . At lethal doses, the keratin assembly–incompetent mice displayed liver lesions faster than wt mice, as indicated histopathologically and by liver‐specific plasma enzyme elevations. The histological changes included centrilobular hemorrhage in all mouse strains. The assembly‐incompetent mice showed a marked vacuolization of periportal hepatocytes. Indistinguishable MC‐LR–induced reorganization of microfilaments was observed in all mice, indicating that this effect on microfilaments is not dependent on the presence of functional K8/K18 networks. At sublethal doses of MC‐LR, all animals had the same potential to recover from the liver damage. Our study shows that K8/K18 filament assembly is regulated in vivo by serine phosphorylation. The absence or occurrence of defective K8/K18 filaments render animals more prone to liver damage, which supports the previously suggested roles of keratin IFs in maintenance of structural integrity.