Chronic ethanol feeding enhances miR-21 induction during liver regeneration while inhibiting proliferation in rats

Abstract

Liver regeneration is an important repair response to liver injury. Chronic ethanol consumption inhibits and delays liver regeneration in experimental animals. We studied the effects of chronic ethanol treatment on messenger RNA (mRNA) and microRNA (miRNA) expression profiles during the first 24 h after two-thirds partial hepatectomy (PHx) and found an increase in hepatic miR-21 expression in both ethanol-fed and pair-fed control rats after PHx. We demonstrate that the increase of miR-21 expression during liver regeneration is more robust in ethanol-fed rats. Peak miR-21 expression occurs at 24 h after PHx in both ethanol-fed and control rats, corresponding to the peak of hepatocyte S phase in control rats, but not in ethanol-exposed livers in which cell cycle is delayed. The induction of miR-21 24 h after PHx in control rats is not greater than the increase in expression of miR-21 due to sham surgery. However, in the ethanol-fed rat, miR-21 is induced to a greater extent by PHx than by sham surgery. To elucidate the implications of increased miR-21 expression during liver regeneration, we employed unbiased global target analysis using gene expression data compiled by our group. Our analyses suggest that miR-21 may play a greater role in regulating gene expression during regeneration in the ethanol-fed rat than in the control rat. Our analysis of potential targets of miR-21 suggests that miR-21 affects a broad range of target processes and may have a widespread regulatory role under conditions of suppressed liver regeneration in ethanol-treated animals.

Integrative microRNA profiling in alcoholic hepatitis reveals a role for microRNA-182 in liver injury and inflammation

“…While most miRNAs identified have never been described in the context of liver disease, others such as miR-21, miR-155 and miR-214 have already been reported as regulators of key pathways in liver diseases. MiR-21 is known to regulate liver fibrosis24–26 and regeneration 27 28. MiR-155 has been described to be expressed in inflammatory cells in alcohol-induced liver disease29 and in animal models of alcohol intake 30.…”

Regulation of the Extrinsic Apoptotic Pathway by MicroRNA-21 in Alcoholic Liver Injury

“…Variable expression of miR-21 has been described in different organ systems and diseases states (25). Indeed, in normal and malignant hepatocytes, miR-21 was shown to be a potent contributor of cell proliferation, but miR-21 induction is not sufficient to regulate cell cycle progression during liver regeneration, particularly in ethanol-fed rats (26). These diverse observations neces- sitate a clear definition of tissue injury-specific expression and function of miR-21 expression.…”

Stress‐Related Alcohol Consumption in Heavy Drinkers Correlates with Expression of miR‐10a, miR‐21, and Components of the TAR‐RNA‐Binding Protein‐Associated Complex

“…These data indicate that miR-21 is an important negative regulator of apoptosis. Previous studies have shown that miR-21 can be down-regulated in vitro by alcohol in neural stem cell/ neural progenitor cells (NSC/NPCs) (Miranda et al, 2010), while chronic ethanol feeding enhances miR-21 induction during liver regeneration (Dippold et al, 2012). …”