PXR agonism decreases plasma HDL levels in ApoE3-Leiden.CETP mice.
Pregnane X receptor (PXR) agonism has been shown to affect multiple steps in both the synthesis and catabolism of HDL, but its integrated effect on HDL metabolism in vivo remains unclear. The aim of this study was to evaluate the net effect of PXR agonism on HDL metabolism in ApoE3-Leiden (E3L) and E3L.CETP mice, well-established models for human-like lipoprotein metabolism. Female mice were fed a diet with increasing amounts of the potent PXR agonist 5-pregnen-3beta-ol-20-one-16alpha-carbonitrile (PCN). In E3L and E3L.CETP mice, PCN increased liver lipids as well as plasma cholesterol and triglycerides. However, whereas PCN increased cholesterol contained in large HDL-1 particles in E3L mice, it dose-dependently decreased HDL-cholesterol in E3L.CETP mice, indicating that CETP expression dominates the effect of PCN on HDL metabolism. Analysis of the hepatic expression of genes involved in HDL metabolism showed that PCN decreased expression of genes involved in HDL synthesis (Abca1, Apoa1), maturation (Lcat, Pltp) and clearance (Sr-b1). The HDL-increasing effect of PCN, observed in E3L mice, is likely caused by a marked decrease in hepatic SR-BI protein expression, and completely reversed by CETP expression. We conclude that chronic PXR agonism dose-dependently reduces plasma HDL-cholesterol in the presence of CETP.
de Haan
Willeke
W
Department of General Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
de Vries-van der Weij
Jitske
J
Mol
Isabel M
IM
Hoekstra
Menno
M
Romijn
Johannes A
JA
Jukema
J Wouter
JW
Havekes
Louis M
LM
Princen
Hans M G
HM
Rensen
Patrick C N
PC
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D015151:Immunoblotting; D008055:Lipids / Q000032:analysis / Q000097:blood; D008074:Lipoproteins / Q000032:analysis / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053318:Apolipoprotein E3; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008055:Lipids; D008074:Lipoproteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D011285:Pregnenolone Carbonitrile