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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2164.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

David Masson; Laurent Lagrost; Anne Athias; Philippe Gambert; Cynthia Brimer-Cline; Lubin Lan; John D. Schuetz; Erin G. Schuetz; Mahfoud Assem

From INSERM U498 (D.M., L.L., A.A., P.G.), Faculté de Médecine, Dijon, France; Pharmaceutical Sciences (C.B.-C., L.L., J.D.S., E.G.S., M.A.), St. Jude Children’s Research Hospital, Memphis, Tenn.

Correspondence to Dr Mahfoud Assem, Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, 332 N. Lauderdale Ave, Memphis, TN 38105-2794. E-mail Mahfoud.Assem{at}stjude.org

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.

To determine the contribution of PXR to the effect of bile acids on plasma lipoproteins, wild-type mice, PXR-deficient mice, and Pxr-null mice expressing human PXR were fed a cholic acid–containing diet. Mouse and human PXR were found to antagonize the cholic acid-mediated decreases in plasma HDL cholesterol and apoA-I.

Key Words: apolipoprotein A-I • bile acids • farnesyl X receptor • high-density lipoproteins • pregnane X receptor • steroid and xenobiotic receptor

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A Role for the Pregnane X Receptor in High-Density Lipoprotein Metabolism

Gregory S. Shelness and Lawrence L. Rudel
Arterioscler. Thromb. Vasc. Biol. 2005 25: 2016-2017. [Extract] [Full Text] [PDF]

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