miRNAs and NAFLD: from pathophysiology to therapy

Abstract

Non-alcoholic fatty liver disease (NAFLD) is associated with a thorough reprogramming of hepatic metabolism. Epigenetic mechanisms, in particular those associated with deregulation of the expressions and activities of microRNAs (miRNAs), play a major role in metabolic disorders associated with NAFLD and their progression towards more severe stages of the disease. In this review, we discuss the recent progress addressing the role of the many facets of complex miRNA regulatory networks in the development and progression of NAFLD. The basic concepts and mechanisms of miRNA-mediated gene regulation as well as the various setbacks encountered in basic and translational research in this field are debated. miRNAs identified so far, whose expressions/activities are deregulated in NAFLD, and which contribute to the outcomes of this pathology are further reviewed. Finally, the potential therapeutic usages in a short to medium term of miRNA-based strategies in NAFLD, in particular to identify non-invasive biomarkers, or to design pharmacological analogues/inhibitors having a broad range of actions on hepatic metabolism, are highlighted.

Deciphering miRNAs’ Action through miRNA Editing

“…Another important feature of the miRNA biology is that a single miRNA can target hundreds of mRNAs, thereby regulating whole networks of proteins. Conversely, one mRNA can be targeted by several miRNAs [16,20]. There are two major consequences associated with these properties: (1) various miRNAs and other factors may compete for binding sites on a particular mRNA (e.g., on the 3 -UTR); (2) variations in the stoichiometry of targets for a specific miRNA, and localization of these targets within distinct cell compartments, can deeply affect the expected interaction between the miRNA and a particular mRNA.…”

“…In this regard, miRNAs can also traffic between various intracellular compartments (e.g., nucleus, cytoplasm, stress granules and mitochondria) under stress conditions (e.g., starvation or hypoxia), thereby either modulating transcriptional/translational rates of target mRNAs within specific intracellular compartments or being secreted as paracrine factors mediating intercellular communication [4,17,[21][22][23]. In addition, expression of other endogenous competing RNAs (ceRNAs), such as pseudogenes, circular RNAs and long ncRNAs (lncRNAs), can act as "sponges" and impair specific miRNA-mRNA interactions (Figure 1d) [20]. Finally, other cellular factors can interact with mature miRNAs and modulate their activity, as it has been demonstrated for AU-rich element-binding proteins (AUBPs) [16].…”

“…In addition, since SRDE is currently not used to edit miRNAs, whether this approach is applicable to small size RNAs remains to be evaluated. Finally, a powerful alternative to investigate the functional relevance of miRNA editing remains to be the usage of synthetic modified oligonucleotides mimicking or inhibiting the edited miRNA of interest, one which can efficiently be incorporated in vitro by cultured cells or in vivo following venous injections [20,70].…”

“…The relevance of miRNA editing in metabolic diseases has not been currently evaluated, but miRNAs are playing key roles in these disorders (see, for example, [20]) and several lines of evidence indicate that RNA editing enzymes might represent key regulators of metabolic processes [20]. For instance, ADAR1 and ADAR2 are upregulated and RNA editing is increased in β-cells of the pancreases of diet-induced obese and insulin-resistant mice [123].…”

Dysregulated CD4+ T Cells and microRNAs in Myocarditis

“…However, recent studies show that pri-miRNAs can also be transcribed by RNA polymerase III (99), and certain debranched introns that structurally mimic pre-miRNAs can also enter the miRNAprocessing pathway (100). In addition, there is evidence that passenger strands can also be incorporated into RISC and trigger gene silencing (101,102).…”