on August 25, 2005
Published online before print August 25, 2005, doi: 10.1161/01.ATV.0000183674.88817.fb
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 11, 2005
Accepted on August 2, 2005
Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid-Mediated Changes in Plasma Lipoprotein Profile
David Masson ;
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.
* To whom correspondence should be addressed. 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 apo A-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/apo A-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 apo A-I, and magnification of PXR/SXR-mediated changes may constitute a new mean to counteract the effects of bile acids on plasma lipoproteins.
Key words: apolipoprotein A-I • bile acids • farnesyl X receptor • high-density lipoproteins • pregnane X receptor • steroid and xenobiotic receptor
Related Article:
- 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]
This article has been cited by other articles:
 |
|
 |
|
  C. Zhou, N. King, K. Y. Chen, and J. L. Breslow Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice J. Lipid Res., October 1, 2009; 50(10): 2004 - 2013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Li, W. Chen, and J. Y. L. Chiang PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine J. Lipid Res., February 1, 2007; 48(2): 373 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Shelness and L. L. Rudel A Role for the Pregnane X Receptor in High-Density Lipoprotein Metabolism Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2016 - 2017. [Full Text] [PDF]
|
|