Polycyclic aromatic hydrocarbons-induced suppression of the PPARα/ACAA1 axis drives hepatic steatosis: Integrating epidemiology, network toxicology, and experimental validation.

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is a common liver condition linked to chronic hepatic dysfunction and systemic metabolic disorders. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and persistent environmental pollutants associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, underlying molecular mechanisms linking PAH exposure to hepatic steatosis remain incompletely elucidated.

OBJECTIVES

This study aimed to clarify the association between PAHs exposure and NAFLD and unravel the core molecular pathways driving PAHs-induced hepatic lipid metabolism dysfunction.

METHODS

Cross-sectional analyses were performed using data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES) to investigate the associations of urinary PAH metabolites with NAFLD prevalence, hepatic steatosis index (HSI), and serum metabolic indicators. The relationships between PAHs and metabolic indicators were further validated in participants from the Preconception Reproductive Health and Birth Outcome Cohort (PREBIC). We then integrated network toxicology, bioinformatics, and both in vivo and in vitro models to elucidate the molecular pathways through which benzo[a]pyrene (BaP), a prototype PAHs, drives hepatic steatosis.

RESULTS

Analyses of NHANES data revealed significant positive associations between PAHs exposure and NAFLD incidence, the hepatic steatosis index (HSI), and serum triglyceride (TG) level. Validation in the PREBIC cohort consistently confirmed the robust association between PAHs exposure and increased TG level. Elevated serum TG levels emerged as a key metabolic indictor of PAHs-induced hepatic steatosis. Network toxicology revealed that PPARα is a key molecular involved in lipid metabolism disruption by BaP, contributing to NAFLD. Integrated bioinformatics analyses further revealed that the binding of BaP to PPARα represses the expression of the downstream gene ACAA1. In vivo and in vitro experiments confirmed that BaP inhibits PPARα signaling, impairing peroxisomal function and fatty acid degradation and thus, leadings to hepatic lipid accumulation.

CONCLUSION

PAHs exposure is associated with hepatic steatosis and elevated serum TG level, and PPARα/ACAA1 axis suppression constitutes a key pathway through which BaP disrupts hepatic lipid metabolism. This study provides novel insights into the environmental etiology of NAFLD and identifies the PPARα/ACAA1 axis as a potential therapeutic target for PAHs-related NAFLD.