Adaptation to ethanol dysregulates hepatic miRNA expression and alters the dynamic response of miRNAs during liver regeneration

MicroRNAs (miRNAs) are short, non-coding RNAs which post-transcriptionally regulate their target messenger RNAs by translational inhibition and/or mRNA destabilization and degradation. miRNAs have been implicated in the regulation of cell cycle, metabolism, development, cancer, and responses to toxins. Adaptation to chronic ethanol treatment of rats results in a changed functional state of the liver and greatly inhibits its regenerative ability, which may contribute to the progression of alcoholic liver disease. Chronic ethanol consumption alters the hepatic miRNA expression profile such that, for instance, the response of several metabolism-associated miRNAs occurs during long-term adaptation to ethanol. Additionally, the dynamic miRNA program during liver regeneration in response to partial hepatectomy is altered in the chronically ethanol-fed rat and these differences reflect, in part, differences in miRNA expression between the ethanol-adapted and control livers at the baseline state prior to partial hepatectomy. miR-21 is pro-proliferative in many contexts, most notably cancer. We find miR-21 expression to increase during liver regeneration following partial hepatectomy. However, the induction of miR-21 is more robust in the livers from regeneration-inhibited ethanol-fed animals compared to the controls. Global gene expression analyses of predicted miR-21 targets suggest that miR-21 induction has a greater effect in the remnant of the ethanol-fed rat than in that of the control rat. Additionally, our analysis suggests that miR-21 may have a widespread regulatory role and a range of effects that are not predominantly associated with the regulation of cell proliferation during inhibited regeneration in the liver of the ethanol-fed rat. Inhibition of miR-21 in vivo does not affect DNA synthesis or expression of cell cycle markers through S phase following partial hepatectomy. However, miR-21 inhibition may affect later stages of the cell cycle. Our data also suggest that few predicted targets of miR-21 are affected by miR-21 inhibition, indicating that the actions of miR-21 are context dependent