Circulating micro-RNA Profile in Nonalcoholic Fatty Liver Disease: Potential Biomarkers and its role in the modulation of the metabolic syndrome?

PIROLA CJ; FERNANDEZ GIANOTTI T; BURGUEÑO A,; CASTANO G; SOOKOIAN S

Washington

Congreso; The Liver Meeting 2013; 2013

The American Association for the Study of Liver Diseases

MicroRNAs (miRNAs) are very small non-coding RNA molecules that have emerged as key regulators of gene expression and metabolism. Circulating miRNAs are present in clinical samples in a remarkably stable form that can be used as potential disease biomarkers; circulating miRNAs have also a strong potential as endocrine signalling molecules. We first aimed to characterize the circulating miRNA profile in patients with NAFLD proven through biopsy in a case-control design. We also aimed to explore the differential expression in the liver of candidate miRNAs. Methods: This study was performed in three phases: (i) global serum miRNA profiling using a 84-miRNA array by real-time RT-PCR (n=48 participants), (ii) independent validation of selected miRNAs (n=86), and (iii) evaluation of liver expression of candidate miRNAs (n=52). Phase (i) and (ii) were conducted using independent groups of patients; phase (iii) involved liver tissue of patients recruited in phase (ii). Results: the comparison of global serum miRNA profile among patients with simple steatosis (SS), NASH and controls showed at least three up-regulated miRNAs including, miRNA-122a (7.2 fold change NASH vs. controls and 2.3 fold change NASH vs. SS), miRNA-192 (4.4 fold change NASH vs. controls) and miRNA-19b (2.1 fold change NASH vs. controls and 4.2 fold change SS vs. controls). These results were replicated in a second set of serum samples, including control subjects (n=20) and 65 NAFLD patients. Both, miRNA-122a (involved in lipid metabolism) and miRNA-192 (involved in TGF-β1 signaling) were significantly associated with the histological progression of NAFLD (regression analysis for an ordinal multinomial distribution: p=0.006 and p=0.03, respectively). Serum miRNA-122a levels were significantly correlated with plasma triglycerides (R: 0.32, p=0.006), AST (R: 0.5, p=0.04), ALT (R: 0.4, p=0.0004) levels, and liver fibrosis (R: 0.3, p=0.02). In addition, serum miRNA-19b was significantly up-regulated in NASH patients in comparison with controls, and significantly correlated with plasma glucose levels (R: 0.26, p=0.02), BMI (R: 0.4, p=0.0004) and biomarkers of atherosclerosis (sICAM1 R: 0.43, p=0.04). Of note, liver miRNA-122a expression was 10 fold down-regulated in NASH patients in comparison with SS (p=0.03). In conclusion: dysregulated miRNA-122 and 192 expression is associated with NAFLD disease progression. Circulating levels of miRNA-19b, which is a regulator of nuclear factor-κB activity, is a novel candidate involved in the cardiovascular phenotype of NAFLD patients.