Abstract 531: Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

Abstract

Objective: Recent studies have associated endocrine disrupting chemical (EDC) exposure with the increased risk of cardiovascular disease (CVD) in humans, but the underlying mechanisms responsible for these associations remain elusive. Many EDCs have been implicated in activating the nuclear receptor pregnane X receptor (PXR) which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. This study aims to investigate the potential role of PXR in lipid homeostasis. Approach and Results: We identified tributyl citrate (TBC), one of a large group of FDA-approved plasticizers for pharmaceutical or food applications, as a potent and selective PXR agonist. TBC efficiently activated PXR and induced PXR target gene expression in vitro and in vivo . Interestingly, TBC was an intestine-specific PXR ligand but did not affect hepatic PXR activity. Exposure to TBC increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice. TBC-mediated PXR activation stimulated the expression of the cholesterol transporter Ni emann-Pick C1-Like 1 (NPC1L1) in the intestine. Promoter analysis revealed a DR-4-type of PXR-response element in the human NPC1L1 promoter and TBC promoted PXR recruitment onto the NPC1L1 promoter. Consistently, TBC treatment significantly increased cholesterol uptake by human and murine intestinal cells and deficiency of PXR blocked TBC-elicited cholesterol uptake. Conclusions: Our results established an important role of intestinal PXR in linking EDC exposure and hyperlipidemia. These findings provide critical mechanistic insight for understanding the adverse effects of EDCs on lipid homeostasis and CVD risk in humans.