Fine particulate matter disrupts bile acid homeostasis in hepatocytes via binding to and activating farnesoid X receptor.

ABSTRACT

Fine particulate matter (PM2.5)-induced metabolic disorders have attracted increasing attention, however, the underlying molecular mechanism of PM2.5-induced hepatic bile acid disorder remains unclear. In this study, we investigated the effects of PM2.5 components on the disruption of bile acid in hepatocytes through farnesoid X receptor (FXR) pathway. The receptor binding assays showed that PM2.5 extracts bound to FXR directly, with half inhibitory concentration (IC50) value of 21.7 µg/mL. PM2.5 extracts significantly promoted FXR-mediated transcriptional activity at 12.5 µg/mL. In mouse primary hepatocytes, we found PM2.5 extracts (100 µg/mL) significantly decreased the total bile acid levels, inhibited the expression of bile acid synthesis gene (Cholesterol 7 alpha-hydroxylase, Cyp7a1), and increased the expression of bile acid transport genes (Multidrug resistance associated protein 2, Abcc2; and Bile salt export pump, Abcb11). Moreover, these alterations were significantly attenuated by knocking down FXR in hepatocytes. We further divided the organic components and water-soluble components from PM2.5, and found that two components bound to and activated FXR, and decreased the bile acid levels in hepatocytes. In addition, benzo[a]pyrene (B[a]P) and cadmium (Cd) were identified as two bioactive components in PM2.5-induced bile acid disorders through FXR signaling pathway. Overall, we found PM2.5 components could bind to and activate FXR, thereby disrupting bile acid synthesis and transport in hepatocytes. These new findings also provide new insights into PM2.5-induced toxicity through nuclear receptor pathways.