Integrated high-throughput miRNomics and lipidomics in mice with altered lipoprotein metabolism.

Abstract

BACKGROUND AND AIMS: With the aim of increasing our knowledge on the mutual interplay between miRNAs and lipids, which is still limited, a novel approach integrating miRNomic and lipidomic data gathered from mice with specific lipid traits was explored. METHODS: miRNomic and lipidomic analyses were previously performed in wild-type, Pcsk9 and Ldlr knockout mice fed normal laboratory diet or Western diet. miRNAs were high-throughput sequenced in liver, aorta, white adipose tissue, duodenum, jejunum, ileum and brain, whereas lipids were quantified by high-throughput mass-spectrometry in liver, aorta and plasma. miRNA expression levels were tested for correlation with each lipid measurement in different samples, and correlations were selected based on strict stringency criteria. In vitro experiments with miRNA mimics or inhibitors in mouse hepatoma cells were performed to validate correlations. RESULTS: Correlation analyses between miRNA expression levels and lipid concentrations in the different experimental conditions led to the selection of miRNAs potentially playing a major role in the regulation of lipid levels. Correlations mainly clustered in liver. Among selected miRNAs, some were already known to be related to lipid metabolism (miR-33, miR-210 and miR-21a) whereas others, including miR-431-5p, miR-434-3p, miR-434-5p and miR-677-5p had never been associated to lipidome perturbations before. In vitro experiments allowed to highlight a possible role of miR-431-5p andmiR-677-5p in the modulation of cholesterol and triglyceride concentrations. CONCLUSIONS: This study bridged miRNomic and lipidomic data in relevant mouse models, allowing to highlight novel miRNAs potentially playing a role in the modulation of lipid levels.