miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis

Abstract

Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD.

Nutrition and Genetics in NAFLD: The Perfect Binomium

“…Unhealthy diets affect adiposity and may accelerate NAFLD development in both animals and humans by altering miRNAs, which are susceptible to environmental challenge. We have previously reported in detail the miRNA signature associated with the spectrum of NAFLD, from simple steatosis towards cirrhosis and HCC [9]. Thus, in this chapter, we will summarize the main findings about miRNAs-diet alteration related to NAFLD onset and progression.…”

“…Epigenetic modifiers in NAFLD can represent novel molecular predictors, which can determine not only the early risk assessment, but also the disease progression and prognosis, providing a new perspective on NAFLD management. Epigenetics is a hereditable but reversible phenomenon that affects chromatin ultrastructure and transcription without modifying DNA sequence in response to environmental cues including DNA methylation, histone modifications and miRNAs targeting mRNA [6,9].…”

“…miRNAs may regulate a wide spectrum of biological processes and metabolic homeostasis, including lipid synthesis, fatty acids and glucose catabolism, inflammation, proliferation, apoptosis and necrosis, which have been known to be epigenetically deregulated in NAFLD, NASH and HCC [126]. Furthermore, it has been shown that circulating miRNAs may mirror the histological features and the molecular events occurring in NAFLD, thus, representing a turning point for non-invasive diagnosis and clinical monitoring of the disease progression [8][9][10][11]127,128]. Unhealthy diets affect adiposity and may accelerate NAFLD development in both animals and humans by altering miRNAs, which are susceptible to environmental challenge.…”

“…Epigenetics encompasses a wide number of events such as alterations of DNA nucleotides (i.e., methylation of CpG dinucleotides, known as CpG islands), modifications of histones and regulation of transcription by altering mRNA stability through small RNA molecules such as microRNAs (miRNAs). Therefore, it may provide a new perspective in NAFLD pathogenesis, diagnosis and management [9]. Nonetheless, among the plethora of multiple parallel hits, recent evidence has pointed out the role of intestinal dysbiosis, microbial metabolites and enhanced intestinal permeability in the pathophysiology of fatty liver [10,11].…”

Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD

“…Second, the effect of various genetic variants has not been incorporated into the model at this first step. Third, our current model considers largely transcriptional factors, while both microRNA regulation [82] and post-translational modifications [83] of proteins have been shown to be important in the context of NAFLD. Despite these limitations, this analysis strongly suggests the role of phenotypic plasticity in the development and progression of NAFLD.…”