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.


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.


CONCLUSIONS
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.
Masson
David
D
INSERM U498, Faculté de Médecine, Dijon, France.
Lagrost
Laurent
L
Athias
Anne
A
Gambert
Philippe
P
Brimer-Cline
Cynthia
C
Lan
Lubin
L
Schuetz
John D
JD
Schuetz
Erin G
EG
Assem
Mahfoud
M
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D008076:Cholesterol, HDL / Q000097:blood*; D019826:Cholic Acid / Q000494:pharmacology*; D015536:Down-Regulation / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D019826:Cholic Acid