Changes in gene expression during Mallory body induction in drug-primed mice livers

To clarify the mechanism of Mallory body (MB) formation, we studied changes in gene expression related to MB and hepatocellular proliferation, using a mouse model fed diethyl 1,4-dihydro-1,4,6-trimethyl-3,5-pyridinedicarboxylate(DDC) for 5 month, followed by withdrawal of DDC for 1 month, then refed for 1,3,5 days, which induces MB formation and hepatocellular proliferation (Yuan et el, Hepatology 24;603-621, 1996). Cytokeratin (CK) 55, tissue transglutaminase (TG) and ubiquitin (UB) mRNA expression was increased by DDC-refeeding. c-jun and c-myc mRNAs were also induced. The pattern of c-jun mRNA expression correlated with an increase in CK55 and TG mRNA. c-myc mRNA expression did not correlate. Hepatocyte growth factor-activator (HGF-A) mRNA expression was not increased during MB formation. The expression of peroxisome proliferator activated receptor α (PPARα) and retinoid x receptor α (RXRα) mRNAs were negatively correlated with the expression of CK55, TG and c-jun mRNA. The data suggest the possibility that MB formation may be regulated by the c-jun product as a transcriptional factor through c-jun induced up-regulation of CK55. The stimulation of hepatocellular proliferation may have a different pathway from MB induction. The latter appears to repress the direct hyperplasia pathway related to PPARα and RXRα.