Mallory Body Induction in Drug–Primed Mouse Liver

Abstract

cell-MB phenomenon. 6 Both compounds induce protoporphyThe aim of this study was to determine the various rin accumulation and hepatoma, 7 as well as the disturbances factors that are involved in the induction of Mallory in the cytoskeleton. Most important to the present report, body (MB) formation. A model was developed where MB the empty cell-MB phenomenon can be reproduced in days formation was induced by refeeding either of the drugs of refeeding in livers that have returned partially to normal griseofulvin or diethyl 1,4-dihydro-1,4,6-trimethyl-3,5-after 1-month withdrawal from the drugs. 1,8 pyridinedicarboxylate (DDC). Mice were fed the drugsIn the present study, mice were first primed by 5 months for 5 months, followed by withdrawal of the drugs for 1 of feeding of GF or DDC. MB formation was induced by either month (drug-primed livers). The drugs were refed for 1, GF or DDC. 9 Then, the mice were fed the diet without GF or 3, 5, 7, or 11 days. Early MBs first appeared as small, DDC for 1 month to allow the MBs to largely disappear. The enlarged aggregates of filaments in the perinuclear or mice were then refed GF or DDC for 1, 3, 5, 7, or 11 days. pericanalicular location on the third day of refeeding.The subsequent reappearance of MBs in the liver and the Mature MBs appeared on the fifth day of refeeding. MBs changes in the liver cytokeratins were measured sequenreached maximum concentration on day 5 of refeeding.tially. We found that MBs reformed beginning at 3 days of Western blots showed a progressive increase in the cytorefeeding. The liver cell cytokeratin proteins abruptly inkeratin proteins (CK49 and CK55) and actin while recreased on the third day of refeeding. Liver regeneration also feeding the drugs. Liver cell regeneration, as indicated increased on the third day of refeeding, as indicated by the by the percent of proliferating cell nuclear antigen level of proliferating cell nuclear antigen (PCNA) labeling of (PCNA)-positive nuclei, increased on the third day of hepatocytic nuclei. However, this did not correlate with the refeeding. However, there was no correlation between level of MB expression. An increase in ubiquitin conjugates, the frequency of MBs and the percent of PCNA-positive as indicated by an increase in the ubiquitin smear observed nuclei. It is concluded that MB formation is not related in Western blots made from whole liver homogenates, correto the liver cell regeneration response to injury but lated with the number of ubiquinated MBs. The results suprather involves a separate regulation pathway. The MBs port the hypothesis that ubiquitination of partially unfolded were heavily ubiquitinated and were associated with incytokeratin proteins is involved in their aggregation to form creased ubiquitin-protein conjugates as indicated byMBs. These results have been reported in part in an abWestern blotting, suggesting that ubiquitinization of cystract. 10 tokeratin protein are involved in the formation of MB aggregation. (HEPATOLOGY 1996;24:603-612.) MATERIALS AND METHODS Denk et ...

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

“…Differences in the phosphorylation pattern of MBs were more clearly revealed in reintoxicated mice where newly formed MBs could be studied. 63 In these mice 8250 and 5B3 strongly reacted with small MB granules at the intersections of the cytokeratin IF network, representing the earliest detectable phase of MB formation. The phosphorylation of the epitopes recognized by these two antibodies may, therefore, participate in the initiation of MB formation.…”

Epigenetic mechanisms regulate Mallory Denk body formation in the livers of drug-primed mice

“…All mice were treated in a humane manner as approved by the Animal Care Committee at Harbor-UCLA Laboratory BioMedical Research Institute according to the Guidelines of the National Academy of Science. The control mice were fed control diet (Yuan 1996).…”

“…Mallory Denk bodies (MDBs) are cytokeratin-rich inclusion bodies that form in human liver cells, mainly in chronic liver disease and in drug-primed mouse livers (Kachi 1993, Yuan 1996. The diethyl-1, 4-dihydro-2, 4, 6-trimethyl-3, 5-pyridinedicarboxylate (DDC)-drugprimed mouse model was used to study the phenomenon of MDB formation (Yuan 1996).…”

“…The diethyl-1, 4-dihydro-2, 4, 6-trimethyl-3, 5-pyridinedicarboxylate (DDC)-drugprimed mouse model was used to study the phenomenon of MDB formation (Yuan 1996). DDC was fed to mice for 10 weeks, at which time MDBs were formed.…”

Mallory body formation by ethanol feeding in drug-primed mice

“…In recent years, we set up a drug-primed mouse model to study MB formation that involved a first feeding of the drug (griseofulvin or DDC) for 5 months, followed by drug withdrawal for 1 month, and a 7-day drug refeeding. [2][3][4] Most of the MBs disappear after the drug withdrawal, leaving only small dot-like MBs at the hepatocyte periphery. However, while it takes at least 3 months of continuous drug feeding before MBs appear in naive mice, 3,4 MBs reappear after only 3 days of refeeding in drug-primed mice.…”