MicroRNAs: master regulators of ethanol abuse and toxicity?

Abstract

Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.

Figure 1

MicroRNA biogenesis and potential influences of alcohol. Hairpin primary miRNA transcripts are successively cleaved by RNases Drosha and Dicer while undergoing transport from the nucleus to the cytoplasm. Association of the mature miRNA with an Argonaut protein (Ago) directs the complex to complementary target sequences in specific messenger RNAs, leading to their cleavage or disruption of their translation. Ethanol may affect miRNA expression by altering activation of transcription factors (TF) and/or epigenetic modifications of DNA and DNA-associated histone complexes, including methylation (Me) and acetylation (Ac). See text for additional details.

Figure 2

Model for the collaborative role for miR21 and miR335 in shaping fetal NSC/NPC fate in the presence and absence of ethanol. Mir21 is anti-apoptotic, while miR335, its functional antagonist, is pro-apoptotic (see text for details). The model shows that in the absence of ethanol, miR21 and miR335 cooperatively repress gene expression to balance cell survival and proliferation. Ethanol decreases both miRNAs (along with miR153 and miR9), resulting in derepression of gene expression, and consequently, increased cell proliferation while maintaining overall apoptosis resistance. We hypothesize that this increase in proliferation following miR-335 suppression prematurely depletes stem cells from the fetal neuroepithelium.

Figure 3

Model for miRNA involvement in Alcoholic Liver Disease (ALD). ALD can result from both direct actions of ethanol on the liver and indirectly, from ethanol's actions on the enteric epithelium. The indirect mode of action implicates miRNA dysregulation in the gut as a permissive agent for ALD. For example, the ethanol-mediated increase in miR212 leads to increased gut leakiness by disrupting the expression of key enteric tight junction scaffolding proteins like ZO-1. The resulting endotoxemia initiates hepatic damage and may lead indirectly to the development of ALD. The composite model is based on research by Tang et al., 2008, and Dolganiuc et al., 2009. See text for additional details.