A Competing Endogenous RNA Network in Circulating Extracellular Vesicles Reveals Differentially-expressed Functional lncRNA in Human Subjects with Metabolic Syndrome

The metabolic syndrome (MetS), a collective cluster of disease risk factors that includes dyslipidemia, obesity, inflammation, hypertension, and insulin resistance, affects numerous people worldwide. Accumulating studies have shown that long-noncoding RNAs (lncRNA) serve as competing endogenous RNA (ceRNA) to play essential roles in regulating gene expression in various diseases. To explore the role of lncRNAs as ceRNAs in MetS, we examined a MetS-associated network in circulating extracellular vesicles (EVs) collected from systemic blood of MetS and control patients (n=5 each). MetS patients showed elevated body-weight, glucose, blood pressure, insulin, liver injury and inflammatory markers levels. In total, 191 differentially-expressed (DE) lncRNAs, 1389 mRNAs, and 138 miRNAs were selected for further analysis. Biological processes and pathway functional enrichment analysis were performed based on the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. LncRNA/mRNA/miRNA ceRNA network was constructed by Cytoscape v3.8 based on the DE-RNAs, and included 13 lncRNAs, 8 miRNAs, and 64 mRNAs. We found that the lncRNA-associated ceRNA network members potentially serve as regulators of central cellular processes and complications of MetS, including cancer. These findings suggest that MetS alters the interactions among the ceRNA network components in circulating EV-specific ceRNA network, and implicate the cargo of circulating EVs in ramifications of MetS. Circulating extracellular vesicles (EVs) collected from systemic blood of metabolic syndrome (MetS) and control patients (n=5 each)