Chronic Real-Ambient PM Exposure Exacerbates Cardiovascular Risk via Amplifying Liver Injury in Mice Fed with a High-Fat and High-Cholesterol Diet.

Epidemiology has associated fine particulate matter (PM) exposure with an increased cardiovascular risk. However, the underlying mechanism, particularly from the liver perspective, remains unclear. Here, the influence of chronic PM exposure on cardiovascular risk in mice fed a high-fat and high-cholesterol diet (HFCD) was studied by using a real-world PM exposure system. Results showed that PM exposure elevated the serum levels of nonhigh-density lipoprotein cholesterol (non-HDL-C) and oxidized low-density lipoprotein (oxLDL) in HFCD-fed mice, demonstrating increased cardiovascular risk. To investigate the molecular mechanism, lipidomics and metabolomics analyses were conducted and revealed that PM exposure enhanced lipid accumulation and disturbed purine metabolism and glutathione metabolism in the liver of HFCD-fed mice, contributing to the elevated non-HDL-C levels and intensified oxidative stress. Moreover, PM exposure increased total cholesterol levels by upregulating expression and downregulating expression in the livers of HFCD-fed mice. The HDL-C level was reduced by inhibiting the hepatic and expression and decreasing the levels of ApoA-I and LCAT. Additionally, the PM-induced pro-oxidative environment impeded the oxLDL clearance and further triggered inflammation, in turn exacerbating oxidative stress and oxLDL production. This study demonstrated a synergy of PM and HFCD on cardiovascular risk and illuminated the molecular mechanism in PM-susceptible populations.