Inhalation exposure to airborne PM attenuates hepatic metabolic pathways through -nitrosylation of the primary ER stress sensor.

Inhalation exposure to airborne fine particulate matter (aerodynamic diameter: <2.5 µm, PM) 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 exposure induces lipid accumulation and inflammation in the liver remains to be further elucidated. In this study, we revealed that inhalation exposure to PM induces nitrosative stress in mouse livers by suppressing hepatic -nitrosoglutathione reductase activities, which leads to -nitrosylation modification of the primary unfolded protein response (UPR) transducer inositol-requiring 1 α (IRE1α), an endoplasmic reticulum-resident protein kinase and endoribonuclease (RNase). -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. Elevation of IRE1α-target miRNAs, due to impaired IRE1α RNase activity by PM-triggered -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. In summary, our study revealed a novel pathway by which PM causes cytotoxicity and promotes MASH-like phenotypes through inducing hepatic nitrosative stress and -nitrosylation of the primary UPR transducer and subsequent elevation of select miRNAs involved in metabolism and inflammation in the liver. Exposure to fine airborne particulate matter PM causes metabolic dysfunction-associated steatohepatitis characterized by hepatic steatosis, inflammation, and fibrosis. Here, we discovered that inhalation exposure to environmental PM induces nitrosative stress in livers by suppressing hepatic -nitrosoglutathione reductase activities, which leads to -nitrosylation of the unfolded protein response transducer IRE1α. -nitrosylation decreases IRE1α-dependent degradation of miRNAs in the livers of mice exposed to PM, leading to downregulation of major regulators of energy metabolism and anti-inflammatory response.