Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder. Strongly linked to obesity and diabetes, NAFLD has the characteristics of complex diseases with substantial heterogeneity. Accordingly, our ability to predict the risk of advanced NAFLD and provide efficient treatment may improve by a better understanding of the relationship between genotype and phenotype. MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in the management of NAFLD. These short non-coding RNA sequences act by partial repression or degradation of targeted mRNAs. Deregulation of miRNAs has been associated with different stages of NAFLD, while their biological role in the pathogenesis remains to be fully understood. Systems biology analyses based on predicted target genes have associated hepatic miRNAs with molecular pathways involved in NAFLD progression such as cholesterol and lipid metabolism, insulin signaling, oxidative stress, inflammation, and pathways of cell survival and proliferation. Moreover, circulating miRNAs have been identified as promising noninvasive biomarkers of NAFLD and linked to disease severity. This rapidly growing field is likely to result in major advances in the pathomechanism, prognostication, and treatment of NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is increasingly common in developed societies, affecting between 20% and 40% of the adult population [1,2]
While NAFLD most often presents as steatosis, 20% to 25% of all NAFLD cases are recognized as nonalcoholic steatohepatitis (NASH), displaying a complex pathology that includes hepatocellular injury, inflammation, and a varying degree of liver fibrosis [5,6]
In a very recent work, various animal models of experimental NAFLD, circulating miR-128-3p levels were markedly associated with the extent of fibrosis and depletion of miR-128-3p content of hepatocellular extracellular vesicles (EVs) with antagomiR-128-3p resulted in diminished stellate cell activation and down-regulation of pro-fibrotic markers [64]
Summary
Nonalcoholic fatty liver disease (NAFLD) is increasingly common in developed societies, affecting between 20% and 40% of the adult population [1,2]. Genome-wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs), which are typically present in 5% or more of the population, with a potential role in wide-ranging disease outcomes including the development and progression of NAFLD [10,11]. Less than 10% of genetic variance is explained by these common variants and it is possible that much of the phenotypic differences result from rare combinations of common genetic variants [13,14]. This latter notion heavily accounts for the role of gene–environment interactions and may explain why we have failed to define NAFLD heterogeneity at the genomic level. The role of miRNAs as pathogenic factors, risk predictors, and therapeutic targets in NAFLD is the subject of this review
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