Association of metabolic signatures of air pollution with MASLD: Observational and Mendelian randomization study.

Background & Aims: Air pollution is a significant public health issue and an important risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms of this association are unknown. Herein, we aimed to identify metabolic signatures associated with exposure to ambient air pollution and to explore their associations with the risk of MASLD.

Methods: We utilized data from the UK Biobank cohort. Annual mean concentrations of PM, PM, NO and NO were assessed for each participant using bilinear interpolation. The elastic net regression model was used to identify metabolites associated with four air pollutants and to construct metabolic signatures. Associations between air pollutants, metabolic signatures and MASLD were analyzed using Cox models. Mendelian randomization (MR) analysis was used to examine potential causality. Mediation analysis was employed to examine the role of metabolic signatures in the association between air pollutants and MASLD.

Results: A total of 244,842 participants from the UK Biobank were included in this analysis. We identified 87, 65, 76, and 71 metabolites as metabolic signatures of PM, PM, NO, and NO, respectively. Metabolic signatures were associated with risk of MASLD, with hazard ratios (HRs) and 95% CIs of 1.10 (1.06-1.14), 1.06 (1.02-1.10), 1.24 (1.20-1.29) and 1.14 (1.10-1.19), respectively. The four pollutants were associated with increased risk of MASLD, with HRs (95% CIs) of 1.03 (1.01-1.05), 1.02 (1.01-1.04), 1.01 (1.01-1.02) and 1.01 (1.00-1.01), respectively. MR analysis indicated an association between PM, NO and NO-related metabolic signatures and MASLD. Metabolic signatures mediated the association of PM, PM, NO and NO with MASLD.

Conclusion: PM, PM, NO and NO-related metabolic signatures appear to be associated with MASLD. These signatures mediated the increased risk of MASLD associated with PM, PM, NO and NO.

Impact And Implications: Air pollution is a significant public health issue and an important risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), however, the mechanism by which air pollution affects MASLD remains unclear. Our study used integrated serological metabolic data of 251 metabolites from a large-scale cohort study to demonstrate that metabolic signatures play a crucial role in the elevated risk of MASLD caused by air pollution. These results are relevant to patients and policymakers because they suggest that air pollution-related metabolic signatures are not only potentially associated with MASLD but also involved in mediating the process by which PM, PM, NO, and NO increase the risk of MASLD. Focusing on changes in air pollution-related metabolic signatures may offer a new perspective for preventing air pollution-induced MASLD and serve as protective measures to address this emerging public health challenge.