Exposure to Ambient Gaseous Pollutants, Serum miRNA Networks, Lipid Metabolism, and Non-Alcoholic Fatty Liver Disease in Young Adults

Abstract

Background and Aim: Exposure to gaseous ambient air pollutants (GP) has been associated with altered lipid metabolism in young adults. MicroRNA (miRNA) networks regulate gene expression and may mediate this relationship. This work aimed to investigate associations of serum miRNA networks with GP, lipid metabolism, and non-alcoholic fatty liver disease (NAFLD) in young adults. Methods: Participants were 124 young adults (17-22 years) from the Metabolic and Asthma Incidence Research (Meta-AIR) cohort. Residential GP exposure (nitrogen dioxide [NO₂]; 24-hour and 8-hour maximum ozone [O₃]; redox-weighted oxidative capacity [Ox]) was spatially interpolated from monitoring stations via inverse-distance-squared weighting. Liver fat was imaged by MRI and NAFLD was defined by ≥5.5% hepatic fat fraction. Serum miRNAs were assayed via NanoString and networks were constructed by weighted gene correlation network analysis (WGCNA). The first eigenvector (z-score) of each network represents the similarity of an individual’s miRNA profile to a given network. Multivariable linear and logistic regression models adjusted for age, sex, ethnicity, and body mass index. Effect estimates are scaled to one standard deviation of exposure. Pre-specified metabolic pathways pertinent to lipid metabolism were examined for enrichment with DIANA-mirPath which extracts experimentally-validated mRNA targets from TarBase and facilitates KEGG pathway analysis. Results: Prior-month 24-hr O₃ and Ox and prior-year NO₂ were inversely associated with the miRNA eigenvector (β=-0.018, p=0.046; β=-0.016, p=0.026; β=-0.019, p=0.022, respectively) of the network comprised of miR-130a-3p, miR-148b-3p, miR-191-5p, miR-199-3p, miR-223-3p, miR-23a-3p, and miR-320e. This miRNA eigenvector was also inversely associated with LDL-cholesterol (β=-6.26, p=0.028) and associated with lower odds of NAFLD (OR=0.37, p=0.007). The mRNA targets of these miRNAs were enriched in the fatty acid biosynthesis pathway (p<0.001). Conclusions: Exposure to GP may contribute to dysregulated lipid metabolism and NAFLD risk among young adults by perturbation of miRNA networks governing fat metabolism. Keywords: microRNA, biomarker, NAFLD, ozone, NO₂, air pollution