Chronic Real-Ambient PM_2.5 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_2.5) exposure with an increased cardiovascular risk. However, the underlying mechanism, particularly from the liver perspective, remains unclear. Here, the influence of chronic PM_2.5 exposure on cardiovascular risk in mice fed a high-fat and high-cholesterol diet (HFCD) was studied by using a real-world PM_2.5 exposure system. Results showed that PM_2.5 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_2.5 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_2.5 exposure increased total cholesterol levels by upregulating Hmgcr expression and downregulating Cyp7a1 expression in the livers of HFCD-fed mice. The HDL-C level was reduced by inhibiting the hepatic Abca1 and Abcg1 expression and decreasing the levels of ApoA-I and LCAT. Additionally, the PM_2.5-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_2.5 and HFCD on cardiovascular risk and illuminated the molecular mechanism in PM_2.5-susceptible populations.