Deficiency of PXR decreases atherosclerosis in apoE-deficient mice

The pregnane X receptor (PXR, also known as SXR) is a nuclear hormone receptor activated by xenobiotics as well as diverse sterols and their metabolites. PXR functions as a xenobiotic sensor to coordinately regulate xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. Recent evidence indicates that PXR may also play an important role in lipid homeostasis and atherosclerosis. To define the role of PXR in atherosclerosis, we generated PXR and apoE double knockout (PXR−/−apoE−/−) mice. Here we show that deficiency of PXR did not alter plasma triglyceride and cholesterol levels in apoE−/− mice. However, PXR−/−apoE−/− mice had significantly decreased atherosclerotic cross-sectional lesion area in both the aortic root and brachiocephalic artery by 40% (P < 0.01) and 60% (P < 0.001), respectively. Interestingly, deficiency of PXR reduced the expression levels of CD36, lipid accumulation, and CD36-mediated oxidized LDL uptake in peritoneal macrophages of PXR−/−apoE−/− mice. Furthermore, immunofluorescence staining showed that PXR and CD36 were expressed in the atherosclerotic lesions of apoE−/− mice, and the expression levels of PXR and CD36 were diminished in the lesions of PXR−/−apoE−/− mice. Our findings indicate that deficiency of PXR attenuates atherosclerosis development, which may result from decreased CD36 expression and reduced lipid uptake in macrophages. The pregnane X receptor (PXR, also known as SXR) is a nuclear hormone receptor activated by xenobiotics as well as diverse sterols and their metabolites. PXR functions as a xenobiotic sensor to coordinately regulate xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. Recent evidence indicates that PXR may also play an important role in lipid homeostasis and atherosclerosis. To define the role of PXR in atherosclerosis, we generated PXR and apoE double knockout (PXR−/−apoE−/−) mice. Here we show that deficiency of PXR did not alter plasma triglyceride and cholesterol levels in apoE−/− mice. However, PXR−/−apoE−/− mice had significantly decreased atherosclerotic cross-sectional lesion area in both the aortic root and brachiocephalic artery by 40% (P < 0.01) and 60% (P < 0.001), respectively. Interestingly, deficiency of PXR reduced the expression levels of CD36, lipid accumulation, and CD36-mediated oxidized LDL uptake in peritoneal macrophages of PXR−/−apoE−/− mice. Furthermore, immunofluorescence staining showed that PXR and CD36 were expressed in the atherosclerotic lesions of apoE−/− mice, and the expression levels of PXR and CD36 were diminished in the lesions of PXR−/−apoE−/− mice. Our findings indicate that deficiency of PXR attenuates atherosclerosis development, which may result from decreased CD36 expression and reduced lipid uptake in macrophages. Despite enormous research efforts and advances in treatments over the past few decades, atherosclerotic cardiovascular disease remains the leading cause of death in the developed world (1Lusis A.J. Atherosclerosis.Nature. 2000; 407: 233-241Crossref PubMed Scopus (4667) Google Scholar, 2Sanz J. Fayad Z.A. Imaging of atherosclerotic cardiovascular disease.Nature. 2008; 451: 953-957Crossref PubMed Scopus (420) Google Scholar). Nuclear receptors have become attractive targets for the development of therapeutic agents for treatment of atherosclerosis (3Barish G.D. Evans R.M. PPARs and LXRs: atherosclerosis goes nuclear.Trends Endocrinol. Metab. 2004; 15: 158-165Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 4Glass C.K. Going nuclear in metabolic and cardiovascular disease.J. Clin. Invest. 2006; 116: 556-560Crossref PubMed Scopus (82) Google Scholar). A number of nuclear receptors, such as liver X receptor (LXR) and peroxisome proliferator-activated receptors (PPARs), are key regulators of lipid homeostasis and inflammation and play important roles in atherosclerosis development (3Barish G.D. Evans R.M. PPARs and LXRs: atherosclerosis goes nuclear.Trends Endocrinol. Metab. 2004; 15: 158-165Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 4Glass C.K. Going nuclear in metabolic and cardiovascular disease.J. Clin. Invest. 2006; 116: 556-560Crossref PubMed Scopus (82) Google Scholar, 5Hageman J. Herrema H. Groen A.K. Kuipers F. A role of the bile salt receptor FXR in atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 1519-1528Crossref PubMed Scopus (80) Google Scholar, 6Huang W. Glass C.K. Nuclear receptors and inflammation control: molecular mechanisms and pathophysiological relevance.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 1542-1549Crossref PubMed Scopus (103) Google Scholar). The pregnane X receptor (PXR; also known as steroid and xenobiotic receptor, or SXR) is a nuclear receptor activated by a diverse array of endogenous hormones, dietary steroids, pharmaceutical agents, and xenobiotic compounds (7Blumberg B. Sabbagh Jr, W. Juguilon H. Bolado Jr, J. van Meter C.M. Ong E.S. Evans R.M. SXR, a novel steroid and xenobiotic-sensing nuclear receptor.Genes Dev. 1998; 12: 3195-3205Crossref PubMed Scopus (814) Google Scholar, 8Kliewer S.A. Moore J.T. Wade L. Staudinger J.L. Watson M.A. Jones S.A. McKee D.D. Oliver B.B. Willson T.M. Zetterstrom R.H. et al.An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway.Cell. 1998; 92: 73-82Abstract Full Text Full Text PDF PubMed Scopus (1325) Google Scholar, 9Zhou C. Verma S. Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism.Nucl. Recept. Signal. 2009; 7: e001Crossref PubMed Scopus (136) Google Scholar). PXR functions as a xenobiotic sensor that regulates clearance via induction of genes involved in drug and xenobiotic metabolism, including oxidation (e.g., cytochrome P450), conjugation (e.g., glutathione transferase), and transport (e.g., multidrug resistance 1) (9Zhou C. Verma S. Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism.Nucl. Recept. Signal. 2009; 7: e001Crossref PubMed Scopus (136) Google Scholar, 10Kliewer S.A. Goodwin B. Willson T.M. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.Endocr. Rev. 2002; 23: 687-702Crossref PubMed Scopus (724) Google Scholar). The broad response profile of PXR has led to the development of “the steroid and xenobiotic sensor hypothesis.” In the past decade, PXR's function in drug and xenobiotic metabolism has been extensively studied by many laboratories (9Zhou C. Verma S. Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism.Nucl. Recept. Signal. 2009; 7: e001Crossref PubMed Scopus (136) Google Scholar). Recent evidence indicates that PXR may also play an important role in lipid homeostasis and atherosclerosis. Many clinically relevant PXR ligands (e.g., rifampicin, ritonavir) have been shown to affect lipid levels in patients and may have pro-atherogenic effects (11Khogali A.M. Chazan B.I. Metcalf V.J. Ramsay J.H. Hyperlipidaemia as a complication of rifampicin treatment.Tubercle. 1974; 55: 231-233Abstract Full Text PDF PubMed Scopus (20) Google Scholar, 12Carr A. Samaras K. Burton S. Law M. Freund J. Chisholm D.J. Cooper D.A. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.A IDS. 1998; 12: F51-F58Google Scholar, 13Shafran S.D. Mashinter L.D. Roberts S.E. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations.HIV Med. 2005; 6: 421-425Crossref PubMed Scopus (128) Google Scholar, 14Barbaro G. Metabolic and cardiovascular complications of highly active antiretroviral therapy for HIV infection.Curr. HIV Res. 2006; 4: 79-85Crossref PubMed Scopus (71) Google Scholar, 15Zhou C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). In to an important role in xenobiotic metabolism, PXR by the uptake CD36 and such as and J. H. H. S. Evans R.M. W. A novel pregnane X and Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. J. J.H. S. S. S. et is a of and in 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). also that of PXR CD36 expression and lipid in peritoneal macrophages of wild-type and apoE knockout mice C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). PXR regulate by in decreased levels of active and reduced triglyceride A. M. S. F. W. Moore D.D. drug metabolism and lipid receptor and pregnane X receptor 2008; PubMed Scopus Google Scholar). and have shown that of PXR also the expression of genes involved in lipid including and in including or LDL receptor knockout mice (9Zhou C. Verma S. Blumberg B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism.Nucl. Recept. Signal. 2009; 7: e001Crossref PubMed Scopus (136) Google Scholar, W. J. M. PXR plasma levels in 2009; PubMed Scopus Google Scholar, M. B. M. Activation of the nuclear receptor PXR plasma levels and induces in LDL receptor knockout 2009; 6: PubMed Scopus Google Scholar). indicate that PXR cholesterol and lipid homeostasis of PXR has been to affect plasma lipid levels in Activation of PXR by treatment plasma cholesterol and levels in mice and levels in mice mice, a for metabolism W. J. M. PXR plasma levels in 2009; PubMed Scopus Google Scholar). that of PXR by apoE−/− mice the PXR levels cholesterol levels C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). showed that of PXR plasma triglyceride levels LDL cholesterol levels in mice M. B. M. Activation of the nuclear receptor PXR plasma levels and induces in LDL receptor knockout 2009; 6: PubMed Scopus Google Scholar). treatment also plasma triglyceride levels in apoE−/− mice M. B. M. Activation of the nuclear receptor PXR plasma levels and induces in LDL receptor knockout 2009; 6: PubMed Scopus Google Scholar). Interestingly, a of indicates that in PXR affect plasma lipid levels in and PXR were to significantly affect plasma LDL cholesterol levels M. The of in genes bile and bile metabolic on cholesterol levels in the 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). of the evidence that of PXR may regulate lipid homeostasis and affect atherosclerosis The of PXR as a xenobiotic sensor has an important for mechanisms which and nuclear receptors that regulate lipid metabolism and inflammation have been extensively studied for their roles in atherosclerosis (3Barish G.D. Evans R.M. PPARs and LXRs: atherosclerosis goes nuclear.Trends Endocrinol. Metab. 2004; 15: 158-165Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 4Glass C.K. Going nuclear in metabolic and cardiovascular disease.J. Clin. Invest. 2006; 116: 556-560Crossref PubMed Scopus (82) Google Scholar). However, the role of PXR in atherosclerosis remains to In we that of PXR by apoE−/− mice the PXR significantly atherosclerosis C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). To define the role of PXR in atherosclerosis, we generated PXR and apoE double knockout (PXR−/−apoE−/−) mice. Here we show that PXR−/−apoE−/− mice had significantly decreased atherosclerotic cross-sectional lesion area in both the aortic root and brachiocephalic plasma lipid peritoneal macrophages from PXR−/−apoE−/− mice showed reduced expression of CD36 and lipid apoE−/− mice. of PXR also decreased CD36-mediated oxidized LDL uptake in peritoneal macrophages. Furthermore, immunofluorescence staining showed that PXR in the atherosclerotic lesions of apoE−/− mice, and the expression levels of CD36 were diminished in the lesions of PXR−/−apoE−/− mice. Our findings indicate that deficiency of PXR attenuates atherosclerosis development, which may result from decreased expression of CD36 and reduced lipid uptake in macrophages. mice on the were from The mice were generated in the of Evans W. J.L. M. Blumberg B. C.M. Evans R.M. xenobiotic response in mice nuclear receptor 2000; PubMed Scopus Google and were for we were the the C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). PXR−/−apoE−/− mice were generated by apoE−/− mice and on were by the of of in a a and by the and apoE−/− or PXR−/−apoE−/− were and a cholesterol Breslow J.L. of atherosclerosis by in LDL and of lesions of the aortic brachiocephalic and Thromb. Vasc. Biol. 23: PubMed Scopus Google Scholar, S. M. Chen K.Y. Breslow J.L. The effect of on atherosclerosis in mice is reduced expression of PubMed Scopus Google for of the of mice were for the to fasting plasma and mice were by were by and by for The and the and in as C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). and were and in cholesterol and triglyceride were by as C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). from mice and plasma cholesterol were by were also by for in a the to a of in to the by for The cholesterol of To the lesion the aortic were a of the aortic root in the and as C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, Breslow J.L. of atherosclerosis by in LDL and of lesions of the aortic brachiocephalic and Thromb. Vasc. Biol. 23: PubMed Scopus Google Scholar). To atherosclerosis the brachiocephalic the brachiocephalic artery to a of lesions to the were in and from the of the brachiocephalic artery the and C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). from as the and the in an as C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). were the for of and to of expression and the PubMed Scopus Google Scholar). The in are shown in were of and peritoneal macrophages were as C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). for the were in to peritoneal macrophages from were to to or for the and were to from the macrophages on and staining on the macrophages to lipid were as and were D.J. M. A signaling is for Metab. 2006; 4: Full Text Full Text PDF PubMed Scopus Google Scholar, B. et metabolism of cardiovascular disease.Nature. PubMed Scopus Google Scholar). The macrophages on the were of for by and staining were also or CD36 by on of aortic in were in for and for were for reduced by in in for were PXR or CD36 for were and or The were by the were a are expressed as were by for and by the for not A of to To the role of PXR in the development of atherosclerosis, we generated PXR−/−apoE−/− double knockout mice by mice apoE−/− mice. PXR−/−apoE−/− mice are and from apoE−/− mice. To deficiency of PXR atherosclerosis, apoE−/− and PXR−/−apoE−/− mice were a cholesterol for The and has been to atherosclerosis development in apoE−/− or mice and insulin resistance C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, Breslow J.L. of atherosclerosis by in LDL and of lesions of the aortic brachiocephalic and Thromb. Vasc. Biol. 23: PubMed Scopus Google Scholar, S. M. Chen K.Y. Breslow J.L. The effect of on atherosclerosis in mice is reduced expression of PubMed Scopus Google Scholar). of apoE−/− and PXR−/−apoE−/− mice had and fasting levels The effect of deficiency of PXR on plasma lipid and levels shown in deficiency of PXR did not affect plasma triglyceride and and cholesterol levels in PXR−/−apoE−/− mice. In showed that apoE−/− and PXR−/−apoE−/− mice had plasma cholesterol The apoE−/− and PXR−/−apoE−/− mice were of and atherosclerotic lesion were in the aortic root and brachiocephalic artery as shown in mice have a atherosclerotic lesion area of in the aortic root and in the brachiocephalic apoE−/− mice, PXR−/−apoE−/− mice had significantly decreased cross-sectional lesion of 40% the aortic root < 0.01) and 60% the brachiocephalic artery < deficiency of PXR atherosclerosis in apoE−/− mice. To molecular mechanisms which PXR deficiency atherosclerosis, a of atherosclerosis genes were by shown in the expression levels of the including and did not in the liver of PXR−/−apoE−/− mice. In to PXR is also expressed in such as and peritoneal macrophages C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. S. J. M. of function by the pregnane X 2010; PubMed Scopus Google Scholar, N. K. C. J. of the drug and PXR in peripheral and their the expression in and 2005; PubMed Scopus Google Scholar, A. B. D.J. of in peripheral and 2004; Google Scholar, G. A. B. M. S. and expression in from Metab. 2008; PubMed Scopus Google Scholar). play a role in and of macrophages is a or atherosclerosis (1Lusis A.J. Atherosclerosis.Nature. 2000; 407: 233-241Crossref PubMed Scopus (4667) Google Scholar, C.K. J.L. The Full Text Full Text PDF PubMed Scopus Google Scholar). have that of PXR CD36 expression and lipid in peritoneal macrophages of apoE−/− mice, which may to the pro-atherogenic effects of PXR C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). To deficiency of PXR peritoneal macrophages from apoE−/− and PXR−/−apoE−/− mice an for were and to to for staining to lipid levels and in peritoneal macrophages. shown in the lipid and in peritoneal macrophages were reduced in peritoneal macrophages of PXR−/−apoE−/− mice. expression indicates that the CD36 levels were significantly decreased in macrophages from PXR−/−apoE−/− mice immunofluorescence staining showed that CD36 expression decreased in macrophages from PXR−/−apoE−/− mice CD36 is a of the receptor and play an important role in of a in or transport of that is Biol. Full Text PDF PubMed Google Scholar, L. Evans R.M. and uptake of oxidized 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The decreased CD36 expression is decreased lipid in In the expression levels of receptor, and and were not significantly in macrophages from apoE−/− and PXR−/−apoE−/− mice In CD36 shown to uptake of by a in D.J. M. A signaling is for Metab. 2006; 4: Full Text Full Text PDF PubMed Scopus Google Scholar). is a of LDL that has been the important LDL M. K. of the receptor CD36 atherosclerotic lesion development in mice.J. Clin. Invest. 2000; PubMed Scopus Google Scholar). To of the PXR peritoneal macrophages were from PXR−/−apoE−/− and apoE−/− mice and staining showed that the uptake of significantly decreased in peritoneal macrophages from PXR−/−apoE−/− mice, which indicates that deficiency of PXR in The significantly decreased CD36 levels and reduced lipid and uptake in the peritoneal macrophages of PXR−/−apoE−/− mice to the of CD36 in the atherosclerotic PXR has been to expressed in of a novel role for the pregnane X PubMed Scopus Google is not PXR is in atherosclerotic staining showed that PXR is in the lesions of apoE−/− mice not in of PXR−/−apoE−/− mice. the levels of CD36 were decreased in the atherosclerotic lesions of PXR−/−apoE−/− mice apoE−/− mice the decreased atherosclerotic lesions in PXR−/−apoE−/− mice may decreased CD36 expression and in macrophages. shown that clinically relevant PXR ligands affect plasma lipid levels in patients and that of PXR may have pro-atherogenic effects in (11Khogali A.M. Chazan B.I. Metcalf V.J. Ramsay J.H. Hyperlipidaemia as a complication of rifampicin treatment.Tubercle. 1974; 55: 231-233Abstract Full Text PDF PubMed Scopus (20) Google Scholar, 13Shafran S.D. Mashinter L.D. Roberts S.E. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations.HIV Med. 2005; 6: 421-425Crossref PubMed Scopus (128) Google Scholar, 15Zhou C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, J. H. H. S. Evans R.M. W. A novel pregnane X and Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Samaras K. Chisholm D.J. Cooper D.A. of peripheral lipodystrophy, and insulin 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. M. of treatment on serum lipid levels in PubMed Scopus Google Scholar). However, the role of PXR in atherosclerosis has not been In the we the effects of PXR deficiency on the development of atherosclerosis in apoE−/− mice. PXR−/−apoE−/− double knockout mice were and the atherosclerosis lesion were apoE−/− and PXR−/−apoE−/− mice in a PXR−/−apoE−/− mice have plasma lipid levels and cholesterol apoE−/− mice significantly decreased atherosclerotic lesion in both the aortic root and brachiocephalic that CD36 expression and lipid were reduced in peritoneal macrophages from PXR−/−apoE−/− mice. of PXR also decreased uptake in peritoneal which may to diminished CD36 also that PXR and CD36 were expressed in the atherosclerotic lesions of apoE−/− mice, the expression levels of CD36 were diminished in the lesions of PXR−/−apoE−/− mice. To is the to the effects of PXR deficiency on atherosclerosis in that of PXR atherosclerosis in mice C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). Activation of PXR cholesterol levels plasma triglyceride and cholesterol levels C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). The decreased atherosclerosis in PXR−/−apoE−/− mice the pro-atherogenic effects of However, we that the plasma lipid levels and cholesterol were not in PXR−/−apoE−/− mice. Furthermore, PXR deficiency did not alter expression levels of genes such as and involved in lipid the decreased atherosclerosis in PXR−/−apoE−/− mice not by plasma lipid levels and lipid PXR regulate the of CD36, a and of PXR CD36-mediated lipid J. H. H. S. Evans R.M. W. A novel pregnane X and Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). CD36 is also a of the receptor and play an important role in such as lipid uptake and of a in or transport of that is Biol. Full Text PDF PubMed Google Scholar). that of PXR CD36 expression and lipid in peritoneal macrophages of apoE−/− mice C. King N. Chen K.Y. Breslow J.L. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice.J. Lipid Res. 2009; 50: 2004-2013Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). In the the expression levels of CD36 and lipid were significantly decreased in the peritoneal macrophages of PXR−/−apoE−/− mice. of PXR the lipid uptake and of peritoneal macrophages in apoE−/− mice. that PXR ligands and expression and cholesterol in not in such as liver Chen W. PXR induces and regulates cholesterol metabolism in the Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). that deficiency of PXR did not affect the expression levels of and in macrophages. The decreased CD36 expression in macrophages may to the decreased atherosclerosis in PXR−/−apoE−/− mice. The in role of CD36 in atherosclerosis remains and and that of CD36 in atherosclerotic lesion development in apoE−/− mice M. K. of the receptor CD36 atherosclerotic lesion development in mice.J. Clin. Invest. 2000; PubMed Scopus Google Scholar, S. M. of atherosclerotic lesion development in Full Text Full Text PDF PubMed Scopus Google Scholar). However, Moore et showed that mice have atherosclerosis in the aortic McKee M. of lipid uptake via receptor A or CD36 not atherosclerosis in mice.J. Clin. Invest. 2005; PubMed Scopus Google Scholar). the that of CD36 and receptor A atherosclerotic lesion atherosclerotic lesion in apoE−/− mice Moore S.A. M. of and CD36 atherosclerotic lesion in Thromb. Vasc. 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S. et is a of and in 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Jr, A.M. and expression of CD36, the receptor, of peroxisome proliferator-activated Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, of CD36 and expression by Thromb. Vasc. Biol. PubMed Scopus Google Scholar, F. R.M. The role of in and cholesterol Med. 7: PubMed Scopus Google Scholar). is for expression of CD36 in and expression of CD36 is diminished in mice F. R.M. The role of in and cholesterol Med. 7: PubMed Scopus Google Scholar, S. G. K. S. M. Glass C.K. Jr, et of the peroxisome proliferator-activated receptor in mice in expression of and apoE in macrophages and reduced cholesterol Biol. 2002; PubMed Scopus Google Scholar). the and transcriptional may also involved in the of CD36 in the macrophages of PXR−/−apoE−/− mice. Furthermore, we have that PXR regulate expression in a C. A. F. Blumberg B. the steroid and xenobiotic receptor, SXR, and regulate expression of Metab. 2004; PubMed Scopus Google Scholar). PXR may important for expression of CD36 in the not in the Interestingly, of a PXR nuclear receptor, also CD36 expression and lipid in the macrophages of C. H. A.J. FXR deficiency reduced atherosclerosis in Thromb. Vasc. Biol. 2006; PubMed Scopus Google or apoE−/− S. Jr, B. of FXR in and atherosclerosis 2006; PubMed Scopus Google mice. mice, deficiency of FXR plasma cholesterol and triglyceride levels in apoE−/− mice S. Jr, B. of FXR in and atherosclerosis 2006; PubMed Scopus Google and plasma triglyceride levels LDL and levels in mice a C. H. A.J. FXR deficiency reduced atherosclerosis in Thromb. Vasc. Biol. 2006; PubMed Scopus Google Scholar). However, both showed that deficiency of FXR atherosclerosis in mice. is that decreased atherosclerosis in or apoE−/− mice is by mechanisms lipid and to the role of nuclear receptors in and atherosclerosis The mechanisms which PXR atherosclerosis in and in to also to the effects of deficiency of PXR on lipid levels and atherosclerosis in such as mice. for the role of PXR in atherosclerosis for the showed that deficiency of PXR atherosclerosis in In we generated PXR−/−apoE−/− double knockout mice to the role of PXR in atherosclerosis PXR−/−apoE−/− mice had significantly reduced atherosclerosis, which may result from decreased expression of CD36, and reduced lipid uptake in macrophages. Our findings an important role of PXR in atherosclerosis and evidence for a xenobiotic metabolism and atherosclerosis. The and development of PXR an and therapeutic to atherosclerosis. The Breslow for and Evans and Blumberg for and for and for of the cytochrome liver X receptor oxidized LDL peroxisome proliferator-activated receptor pregnane X receptor steroid and xenobiotic receptor