Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid–Mediated Changes in Plasma Lipoprotein Profile

Objective— Modification of lipoprotein metabolism by bile acids has been mainly explained by activation of the farnesyl X receptor (FXR). The aim of the present study was to determine the relative contribution of the pregnane X receptor (PXR), another bile acid–activated nuclear receptor to changes in plasma lipoprotein profile. Methods and Results— Wild-type mice, Pxr-deficient mice, and Pxr-null mice expressing human PXR (Pxr-null SXR-Tg mice) were fed a cholic acid–containing diet, and consequences on plasma lipoprotein profiles and target gene expression were assessed. Cholic acid produced significant decreases in high-density lipoprotein (HDL) cholesterol, plasma apolipoprotein (apo)A-I and hepatic apoA-I mRNA in wild-type mice. Interestingly, the effect of cholic acid was significantly more pronounced in Pxr-deficient mice, indicating that PXR contributes to the weakening of the effect of bile acids on lipoprotein metabolism. Reciprocally, changes in HDL/apoA-I profiles were abolished in Pxr-null SXR-Tg mice in which PXR-responsive genes, particularly those involved in bile acid detoxification were readily activated after cholic acid treatment. Conclusion— PXR expression in mice antagonizes the cholic acid–mediated downregulation of plasma HDL cholesterol and apoA-I, and magnification of PXR/SXR-mediated changes may constitute a new mean to counteract the effects of bile acids on plasma lipoproteins.