Inhalation exposure to airborne PM_2.5 attenuates hepatic metabolic pathways through <i>S</i>-nitrosylation of the primary ER stress sensor

Inhalation exposure to airborne fine particulate matter (aerodynamic diameter: <2.5 µm, PM_2.5) is known to cause metabolic dysfunction-associated steatohepatitis (MASH) and the associated metabolic syndrome. Hepatic lipid accumulation and inflammation are the key characteristics of MASH. However, the mechanism by which PM_2.5 exposure induces lipid accumulation and inflammation in the liver remains to be further elucidated. In this study, we revealed that inhalation exposure to PM_2.5 induces nitrosative stress in mouse livers by suppressing hepatic <i>S</i>-nitrosoglutathione reductase activities, which leads to <i>S</i>-nitrosylation modification of the primary unfolded protein response (UPR) transducer inositol-requiring 1 α (IRE1α), an endoplasmic reticulum-resident protein kinase and endoribonuclease (RNase). <i>S</i>-nitrosylation suppresses the RNase activity of IRE1α and subsequently decreases IRE1α-mediated splicing of the mRNA encoding X-box binding protein 1 (XBP1) and IRE1α-dependent degradation of select microRNAs (miRNAs), including miR-200 family members, miR-34, miR-223, miR-155, and miR-146, in the livers of the mice exposed to PM_2.5. Elevation of IRE1α-target miRNAs, due to impaired IRE1α RNase activity by PM_2.5-triggered <i>S</i>-nitrosylation, leads to decreased expression of the major regulators of fatty acid oxidation, lipolysis, and anti-inflammatory response, including XBP1, sirtuin 1, peroxisome proliferator-activated receptor α, and peroxisome proliferator-activated receptor γ, in the liver, which account at least partially for hepatic lipid accumulation and inflammation in mice exposed to airborne PM_2.5. In summary, our study revealed a novel pathway by which PM_2.5 causes cytotoxicity and promotes MASH-like phenotypes through inducing hepatic nitrosative stress and <i>S</i>-nitrosylation of the primary UPR transducer and subsequent elevation of select miRNAs involved in metabolism and inflammation in the liver.<b>NEW & NOTEWORTHY</b> Exposure to fine airborne particulate matter PM_2.5 causes metabolic dysfunction-associated steatohepatitis characterized by hepatic steatosis, inflammation, and fibrosis. Here, we discovered that inhalation exposure to environmental PM_2.5 induces nitrosative stress in livers by suppressing hepatic <i>S</i>-nitrosoglutathione reductase activities, which leads to <i>S</i>-nitrosylation of the unfolded protein response transducer IRE1α. <i>S</i>-nitrosylation decreases IRE1α-dependent degradation of miRNAs in the livers of mice exposed to PM_2.5, leading to downregulation of major regulators of energy metabolism and anti-inflammatory response.