Ambient NO2 exposure affects hepatic glycolipid metabolism in mice with a sex-dependent property

NO2 is one of the major air pollutants. Exposure to NO2 is associated with various metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD), diabetes, cardiovascular disease, etc. Abnormal hepatic glycolipid metabolism is a key feature of metabolic diseases. However, few studies provide evidence for the effects of NO2 inhalation on hepatic glycolipid metabolism. In this study, female and male C57BL/6 J mice were exposed to NO2 (2.5 ppm, 5 h/day) for 4 weeks using a systemic inhalation exposure system. The results indicated that NO2 exposure increased the levels of hepatic enzymes in serum and led to liver dysfunction in female mice, but not male ones. Especially, female mice developed glycolipid metabolic disorders, including increased blood glucose, decreased hepatic glycogen and glucose tolerance, and increased lipid level in liver and blood. Metabolomic analysis clarified 33 differential metabolites of glycolipids, which were mainly enriched through several pathways, including synthesis and degradation of ketone bodies, fat digestion and absorption, galactose metabolism, fatty acid degradation, and glycerophospholipid metabolism. The mRNA and protein expression implicated that the exposure disrupted glucose metabolism by reducing hepatic glycogen synthesis and increasing gluconeogenesis, and caused lipid deposition by increasing lipogenesis and uptake, thereby increasing lipid oxidation and secretion. The findings highlight the risk of metabolic diseases upon exposure to NO2 in the air.