PXR-mediated organophorous flame retardant tricresyl phosphate effects on lipid homeostasis

An emerging experimental framework suggests that endocrine-disrupting compounds are candidate obesogens. However, this potential effect has not yet been determined for Tricresyl phosphate (TCP), a mass-produced organophosphate flame retardant (OPFR) that has been exposed to human beings in many ways. Many OPFRs, including TCP, have been shown to activate pregnane X receptor (PXR), a nuclear receptor that regulates lipid metabolism. Accordingly, we found that TCP exposure caused lipid accumulation in HepG2 cells in this study. Therefore, to elucidate the role of PXR played in TCP metabolism and promotion of lipid accumulation, HepG2 cells were exposed to different concentrations (5 × 10^-8 to 5 × 10^-5 M) of TCP for 24 h. The enlarged hepatic lipid droplets and increased hepatic triglyceride contents were observed in HepG2 cells after TCP exposure for 24 h. This is the result of a confluence of lipogenesis increase and β-oxidation suppression imposed by PXR activation which was verified by the up regulation of genes in fatty acid (FA) synthesis and the down regulation of genes in β-oxidation. Surface plasmon resonance (SPR) analysis and molecular docking revealed favorable binding mode of TCP to PXR and the knockout of PXR gene with CRISPR/cpf1 system in HepG2 cells abolished TCP-induced triglyceride accumulation, thus underlying the crucial role of PXR in hepatic lipid metabolism resulting from OPFRs exposure. This study enhances our understanding of molecular mechanisms and associations of PXR in lipid metabolism disturbance induced by TCP and provides novel evidence regarding the lipotoxicity effect and potential metabolism pathway of OPFRs.