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Papers In Press, published online ahead of print October 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800608-JLR200

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Journal of Lipid Research, Vol. 50, 2004-2013, October 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice^[S]

Changcheng Zhou, Nakesha King, Kwan Y. Chen and Jan L. Breslow¹

Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10065

¹ To whom correspondence should be addressed. e-mail: breslow{at}rockefeller.edu

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 clinically 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 16-carbonitrile (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 (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 antiatherogenic ApoA-IV and increasing lipid accumulation in macrophages.—Zhou, C., N. King, K. Y. Chen, and J. L. Breslow. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.

Supplementary key words xenobiotic metabolism • cholesterol homeostasis • pregnane X receptor • apolipoprotein

Abbreviations: Apo, apolipoprotein; CYB5R3, cytochrome b5 reductase 3; DHCR7, 7-dehydrocholesterol reductase; MDR1, multidrug resistance protein-1; PCN, pregnenolone 16-carbonitrile; PXR, pregnane X receptor; QPCR, quantitative real-time PCR; SREBP, sterol regulatory element binding protein; SXR, steroid and xenobiotic receptor; WT, wild-type

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