Abstract 12115: Phthalate Substitute Plasticizers Activate PXR and Induce Dyslipidemia in Mice
The pregnane X receptor (PXR) is a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. Many endocrine disrupting chemicals (EDCs) activate PXR, including organochlorine and organophosphate pesticides, alkylphenols, phthalates, polychlorinated biphenyls, bisphenol A and phthalate plasticizers. However, the role of PXR in mediating the pathophysiological effects of EDCs in humans and animals remains elusive. Mounting evidence implicates EDC exposure in the development of chronic human diseases, but the contribution of these EDCs to the etiology of cardiovascular disease (CVD) is poorly understood. In the present study, we identified several widely used phthalate substitute plasticizers used in food packaging materials, medical devices, cosmetics, and pharmaceutical drugs as agonists of PXR. Tributyl citrate (TBC), one of a large group of FDA-approved pharmaceutical plasticizers, is a potent and selective PXR agonist but does not activate other nuclear receptors. TBC can efficiently activate PXR and induce its target gene expression in vitro and in vivo. Short-term TBC exposure increased plasma total cholesterol and atherogenic LDL cholesterol levels in wild-type mice, but not in PXR-deficient mice. Interestingly, TBC is an intestine-specific PXR ligand but does not affect hepatic PXR activity. TBC-mediated PXR activation stimulated the expression of intestinal cholesterol transporter, Niemann Pick-C1 Like 1 (NPC1L1). Chromatin Immunoprecipitation experiments revealed that PXR can bind to the NPC1L1 promoter. Further, TBC treatment also significantly increased NPC1L1 expression and cholesterol uptake in human intestinal cells and murine primary enterocytes. These findings provide critical mechanistic insight for understanding the impact of EDC-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating adverse effects of EDCs on CVD risk in humans.
Author Disclosures: Y. Sui: None. R.N. Helsley: None. S. Park: None. Z. Liu: None. C. Zhou: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.