The pregnane X receptor (PXR; also known as steroid and xenobiotic receptor, or SXR) is a nuclear hormone receptor activated by xenobiotics as well as diverse sterols

This article is available online at http://www.jlr.org The pregnane X receptor (PXR; also known as steroid and xenobiotic receptor, or SXR) is a nuclear hormone receptor activated by xenobiotics as well as diverse sterols and their metabolites ( 1–3 ). In the past decade, the role of PXR as a sensor that coordinately regulates xenobiotic clearance in the liver and intestine has been clearly established. The ligand-receptor complex induces expression of genes involved in drug and xenobiotic metabolism, including oxidation [phase I genes; e.g., cytochrome P450s (CYP)], conjugation [phase II genes; e.g., glucuronyl or glutathione transferase (UDP-glucuronosyltransferase and GST, respectively)], and transport [phase III genes; e.g., multidrug resistance 1 (MDR1/ABCB1)] ( 4–6 ). For instance, PXR plays a central role in the transcriptional regulation of CYP3A4, which is responsible for the metabolism of more than 50% of clinically used drugs. Many clinically relevant PXR ligands have been shown to affect lipid levels in patients. For example, treatment with rifampicin, a PXR ligand used in the clinic for the treatment of tuberculosis, can cause hyperlipidemia ( 7 ), and in one study, treatment for 6 days increased the ratio of lathosterol to cholesterol, indicating increased cholesterol synthesis ( 8 ). Treatment of HIV patients with ritonavir, one of the fi rst commercially available HIV protease inhibitors and a potent PXR activator ( 9 ), caused hyperlipidemia and may be associated with increased risk of cardiovascular disease ( 10–13 ). Long-term treatment of children with the antiepileptic drugs carbamazipine and phenobarbital, both PXR ligands, increase cholesterol levels ( 14 ). Finally, it was recently shown that cafestol, presented in unfi ltered brewed coffee and the most potent Abstract 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 signifi cantly 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 defi cient (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 signifi cantly 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 defi cient mice. J. Lipid Res . 2009. 50: 2004–2013.