Serum miR-4488 as a potential biomarker of lean nonalcoholic fatty liver disease.

Abstract

In lean individuals, nonalcoholic fatty liver disease (NAFLD) is not a benign disease, and these patients have long-term morbidity and mortality similar to those of their nonlean counterparts. Finding biomarkers for noninvasive and early detection is urgent and microRNAs (miRNAs) show potential. The aims of this study were to investigate the potential role of serum miRNAs in the detection of lean NAFLD and to explore the possible pathogenesis of lean NAFLD. A total of 498 patients with NAFLD and 98 healthy controls were included to compare the clinical characteristics of lean NAFLD patients [LNs: body mass index (BMI) <23 kg/m2], nonlean NAFLD patients (NLNs: BMI ≥23 kg/m2) and normal healthy individuals (HIs). A total of 14 serum samples were collected from 4 LNs, 6 NLNs and 4 HIs for high-throughput profiling to identify altered miRNA expression patterns in lean NAFLD. The candidate miRNA, miR-4488, was identified by filtering based on studies in a second independent cohort (31 LNs, 62 NLNs, 72 HIs) that included quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction network analyses were performed to investigate the potential molecular mechanism of miR-4488 in lean NAFLD. LNs were older and had a smaller waist circumference, lower levels of alanine aminotransferase, glutamyl transpeptidase, fasting insulin, and uric acid, lower HOMA-IR score, and higher levels of total cholesterol, high-density lipoprotein cholesterol, and hemoglobin (P<0.05). The serum level of miR-4488 was increased in LNs compared with HIs (P<0.0001) and NLNs (P=0.025). miR-4488 had acceptable performance in predicting [area under the curve (AUC) =0.794, 0.698] lean NAFLD. Moreover, GO and KEGG enrichment analyses revealed that the differentially expressed target genes were mainly involved in choline metabolism in cancer, the tumor-necrosis factor (TNF) signaling pathway and the p53 signaling pathway. PPI analysis identified ARHGAP1, SLC10A1 and SIX5 as the hub genes. Taken together, our findings indicate that serum miR-4488 is a potential biomarker for diagnosing and predicting the pathogenetic mechanisms of lean NAFLD.