| First Author | Zhou C | Year | 2009 |
| Journal | J Lipid Res | Volume | 50 |
| Issue | 10 | Pages | 2004-13 |
| PubMed ID | 19436068 | Mgi Jnum | J:154141 |
| Mgi Id | MGI:4367325 | Doi | 10.1194/jlr.M800608-JLR200 |
| Citation | Zhou C, et al. (2009) Activation of pregnane X receptor induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apolipoprotein E deficient mice. J Lipid Res 50:2004-2013 |
| abstractText | The nuclear hormone receptor pregnane X receptor (PXR) (also called SXR) functions as a xenobiotic sensor to coordinately regulate xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. Although many clinical relevant PXR ligands have been shown to affect cholesterol levels, the role of PXR in cholesterol homeostasis and atherosclerosis has not been thoroughly investigated. Here we report that activation of PXR by feeding the PXR agonist pregnenolone 16a-carbonitrile (PCN) (0.02%) for 2 weeks to wild-type (WT) mice significantly increased total cholesterol levels and atherogenic lipoproteins VLDL and LDL levels, but had no effect in PXR knockout mice (PXR-/-) mice. Chronic PXR activation in atherosclerosis prone apolipoprotein E deficient (ApoE-/-) mice was found to decrease HDL levels and increase atherosclerotic cross sectional lesion area at both the aortic root and in the brachiocephalic artery by 54% (p<0.001) and 116% (p<0.01), respectively. PXR activation significantly regulated genes in the liver involved in lipoprotein transportation and cholesterol metabolism, including CD36, ApoA-IV and CYP39A1, in both WT and ApoE-/- mice. Furthermore, PXR activation can increase CD36 expression and lipid accumulation in peritoneal macrophages of ApoE-/- mice. In summary, PXR activation in WT mice increases levels of the atherogenic lipoproteins VLDL and LDL, whereas in ApoE-/- mice PXR increases atherosclerosis perhaps by diminishing levels of the anti-atherogenic ApoA-IV and increasing lipid accumulation in macrophages. |
