Intracellular and extracellular miRNome deregulation in cellular models of NAFLD or NASH: Clinical implications

• Published in: Nutrition, metabolism, and cardiovascular diseases Vol. 26; no. 12; pp. 1129 - 1139
• Main Authors: Di Mauro, S, Ragusa, M, Urbano, F, Filippello, A, Di Pino, A, Scamporrino, A, Pulvirenti, A, Ferro, A, Rabuazzo, A.M, Purrello, M, Purrello, F, Piro, S
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-12-2016
• Subjects: Cardiovascular; CD36 Antigens - genetics; CD36 Antigens - metabolism; Cell Survival; Ceramides - metabolism; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Computational Biology; Diglycerides - metabolism; FFAs; Gene Expression Profiling - methods; Gene Expression Regulation; Gene Regulatory Networks; Genetic Markers; Hep G2 Cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; HepG2; Humans; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Liver - drug effects; Liver - metabolism; Liver - pathology; microRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; NAFLD; NASH; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Oleic Acid - toxicity; Oligonucleotide Array Sequence Analysis; Palmitic Acid - toxicity; Phosphorylation; Protein Interaction Maps; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; microRNAs; HepG2; NAFLD; FFAs; NASH
• ISSN: 0939-4753; 1590-3729
• DOI: 10.1016/j.numecd.2016.08.004

Abstract Background & aims Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD has the potential to progress through the inflammatory phase of nonalcoholic steatohepatitis (NASH) to fibrosis, cirrhosis, and hepatocellular carcinoma. Identifying patients at risk for this transition is a relevant clinical challenge. The complexity of these phenotypes in vivo made necessary the development of in vitro models in order to dissect the molecular signalling affected in NAFLD and NASH, but also to identify potential circulating biomarkers. Methods and results We profiled the expression of 754 cellular and medium-secreted human miRNAs in HepG2 cells after lipotoxic (Palmitate, model of NASH) or not-lipotoxic stimuli (Oleate-Palmitate, model of NAFLD). Results were validated through Single TaqMan assays. We performed computational analysis of miRNA targets and pathways. Oleate-palmitate treatment induced a variation of 2.8% and 10% of total miRNAs in cells and medium, respectively; palmitate treatment caused 10% and 19% intracellular and extracellular miRNA deregulation, respectively. We validated miR-126, miR-150, miR-223, miR-483-3p, miR-1226*, and miR-1290 deregulation. Through computational analysis, we observed that targets of both intracellular and extracellular DE miRNAs were involved in processes associated with the onset and progression of NAFLD and NASH, such as fatty acid metabolism, apoptosis and inflammation. Conclusions These data would be useful to elucidate the role of miRNAs in the pathogenesis and progression of the NAFLD spectrum, but they also allow the identification of novel potential biomarkers for differential diagnosis to be tested in vivo.