Deciphering the roles of the constitutive androstane receptor in energy metabolism

Acta Pharmacologica Sinica

Volumn 36, Issue 1, 2015, Pages 62-70

  Yan, Jiong ^a   Chen, Baian ^b   Lu, Jing ^b   Xie, Wen ^a,c  

^a UNIVERSITY OF PITTSBURGH   (United States)

^b CAPITAL MEDICAL UNIVERSITY   (China)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

constitutive androstane receptor; energy metabolism; metabolic diseases; nuclear receptor; xenobiotic metabolism

Indexed keywords

CONSTITUTIVE ANDROSTANE RECEPTOR; CELL RECEPTOR; GLUCOSE; TRANSCRIPTION FACTOR;

CHOLESTEROL SYNTHESIS; CIRCADIAN RHYTHM; ENERGY METABOLISM; FATTY ACID SYNTHESIS; GLUCONEOGENESIS; GLUCOSE METABOLISM; GLUCOSE TOLERANCE; HUMAN; INSULIN SENSITIVITY; LIPID METABOLISM; LIPOGENESIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PROTEIN PHOSPHORYLATION; REGULATORY MECHANISM; REVIEW; TRANSCRIPTION REGULATION; XENOBIOTIC METABOLISM; ANIMAL; METABOLISM; PHYSIOLOGY;

ANIMALS; ENERGY METABOLISM; GLUCOSE; HUMANS; LIPID METABOLISM; RECEPTORS, CYTOPLASMIC AND NUCLEAR; TRANSCRIPTION FACTORS;

EID: 84920420772     PISSN: 16714083     EISSN: 17457254     Source Type: Journal    
DOI: 10.1038/aps.2014.102     Document Type: Review

References (111)

1. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 2006; 126: 789-99.
2. Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 2000; 407: 920-3.
3. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA. Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 2002; 62: 638-46.
4. Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 2000; 14: 3014-23.
5. Honkakoski P, Negishi M. Characterization of a phenobarbitalresponsive enhancer module in mouse P450 Cyp2b10 gene. J Biol Chem 1997; 272: 14943-9.
6. Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 1998; 18: 5652-8.
7. Saini SP, Sonoda J, Xu L, Toma D, Uppal H, Mu Y, et al. A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification. Mol Pharmacol 2004; 65: 292-300.
8. Uppal H, Toma D, Saini SP, Ren S, Jones TJ, Xie W. Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice. Hepatology 2005; 41: 168-76.
9. Zhang J, Huang W, Qatanani M, Evans RM, Moore DD. The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. J Biol Chem 2004; 279: 49517-22.
10. Stedman CA, Liddle C, Coulter SA, Sonoda J, Alvarez JG, Moore DD, et al. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci USA 2005; 102: 2063-8.
11. Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, et al. Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 2002; 61: 1-6.
12. Locker J, Tian J, Carver R, Concas D, Cossu C, Ledda-Columbano GM, et al. A common set of immediate-early response genes in liver regeneration and hyperplasia. Hepatology 2003; 38: 314-25.
13. Columbano A, Ledda-Columbano GM, Pibiri M, Cossu C, Menegazzi M, Moore DD, et al. Gadd45β is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia. Hepatology 2005; 42: 1118-26.
14. Moore DD. Nuclear receptors reverse McGarry's vicious cycle to insulin resistance. Cell metabolism 2012; 15: 615-22.
15. Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, et al. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 2005; 19: 1646-53.
16. Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M. Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol 1999; 19: 6318-22.
17. Osabe M, Negishi M. Active ERK1/2 protein interacts with the phosphorylated nuclear constitutive active/androstane receptor (CAR; NR1I3), repressing dephosphorylation and sequestering CAR in the cytoplasm. J Biol Chem 2011; 286: 35763-9.
18. Koike C, Moore R, Negishi M. Extracellular signal-regulated kinase is an endogenous signal retaining the nuclear constitutive active/androstane receptor (CAR) in the cytoplasm of mouse primary hepatocytes. Mol Pharmacol 2007; 71: 1217-21.
19. Sidhu JS, Omiecinski CJ. An okadaic acid-sensitive pathway involved in the phenobarbital-mediated induction of CYP2B gene expression in primary rat hepatocyte cultures. J Pharmacol Exp Ther 1997; 282: 1122-9.
20. Mutoh S, Sobhany M, Moore R, Perera L, Pedersen L, Sueyoshi T, et al. Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal 2013; 6: ra31.
21. Hosseinpour F, Moore R, Negishi M, Sueyoshi T. Serine 202 regulates the nuclear translocation of constitutive active/androstane receptor. Mol Pharmacol 2006; 69: 1095-102.
22. Sueyoshi T, Moore R, Sugatani J, Matsumura Y, Negishi M. PPP1R16A, the membrane subunit of protein phosphatase 1β, signals nuclear translocation of the nuclear receptor constitutive active/androstane receptor. Mol Pharmacol 2008; 73: 1113-21.
23. Saito K, Moore R, Negishi M. p38 Mitogen-activated protein kinase regulates nuclear receptor CAR that activates the CYP2B6 gene. Drug Metab Disposition 2013; 41: 1170-3.
24. Yoshinari K, Kobayashi K, Moore R, Kawamoto T, Negishi M. Identification of the nuclear receptor CAR: HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital. FEBS Lett 2003; 548: 17-20.
25. Kobayashi K, Sueyoshi T, Inoue K, Moore R, Negishi M. Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells. Mol Pharmacol 2003; 64: 1069-75.
26. Kanno Y, Miyama Y, Ando M, Inouye Y. Dependence on the microtubule network and 90-kDa heat shock protein of phenobarbitalinduced nuclear translocation of the rat constitutive androstane receptor. Mol Pharmacol 2010; 77: 311-6.
27. Timsit YE, Negishi M. Coordinated regulation of nuclear receptor CAR by CCRP/DNAJC7, HSP70 and the ubiquitin-proteasome system. PLoS One 2014; 9: e96092.
28. Rencurel F, Stenhouse A, Hawley SA, Friedberg T, Hardie DG, Sutherland C, et al. AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line. J Biol Chem 2005; 280: 4367-73.
29. Rencurel F, Foretz M, Kaufmann MR, Stroka D, Looser R, Leclerc I, et al. Stimulation of AMP-activated protein kinase is essential for the induction of drug metabolizing enzymes by phenobarbital in human and mouse liver. Mol Pharmacol 2006; 70: 1925-34.
30. Shindo S, Numazawa S, Yoshida T. A physiological role of AMPactivated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction. Biochem J 2007; 401: 735-41.
31. Blättler SM, Rencurel F, Kaufmann MR, Meyer UA. In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase. Proc Natl Acad Sci USA 2007; 104: 1045-50.
32. Shizu R, Shindo S, Yoshida T, Numazawa S. MicroRNA-122 downregulation is involved in phenobarbital-mediated activation of the constitutive androstane receptor. PLoS One 2012; 7: e41291.
33. Hung CM, Su YH, Lin HY, Lin JN, Liu LC, Ho CT, et al. Demethoxycurcumin modulates prostate cancer cell proliferation via AMPKinduced down-regulation of HSP70 and EGFR. J Agric Food Chem 2012; 60: 8427-34.
34. Jung JH, Lee JO, Kim JH, Lee SK, You GY, Park SH, et al. Quercetin suppresses HeLa cell viability via AMPK-induced HSP70 and EGFR down-regulation. J Cell Physiol 2010; 223: 408-14.
35. Kim KY, Baek A, Hwang JE, Choi YA, Jeong J, Lee MS, et al. Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation. Cancer Res 2009; 69: 4018-26.
36. Min G, Kemper JK, Kemper B. Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo. J Biol Chem 2002; 277: 26356-63.
37. Guo D, Sarkar J, Ahmed MR, Viswakarma N, Jia Y, Yu S, et al. Peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP) but not PPAR-interacting protein (PRIP) is required for nuclear translocation of constitutive androstane receptor in mouse liver. Biochem Biophys Res Commun 2006; 347: 485-95.
38. Chang TK, Waxman DJ. Synthetic drugs and natural products as modulators of constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Drug Metab Rev 2006; 38: 51-73.
39. Patel RD, Hollingshead BD, Omiecinski CJ, Perdew GH. Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor levels in murine and human liver. Hepatology 2007; 46: 209-18.
40. Pascussi JM, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ. Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. Mol Pharmacol 2000; 58: 1441-50.
41. Ooe H, Kon J, Oshima H, Mitaka T. Thyroid hormone is necessary for expression of constitutive androstane receptor in rat hepatocytes. Drug Metab Disposition 2009; 37: 1963-69.
42. Qatanani M, Zhang J, Moore DD. Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 2005; 146: 995-1002.
43. Saito K, Kobayashi K, Mizuno Y, Furihata T, Chiba K. Constitutive androstane/active receptor is a target of retinoic acid receptor in humans. Biochem Pharmacol 2010; 80: 129-35.
44. Wieneke N, Hirsch-Ernst KI, Kuna M, Kersten S, Püschel GP. PPARα-dependent induction of the energy homeostasis-regulating nuclear receptor NR1i3 (CAR) in rat hepatocytes: potential role in starvation adaptation. FEBS Lett 2007; 581: 5617-26.
45. Ding X, Lichti K, Kim I, Gonzalez FJ, Staudinger JL. Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor α, and the coactivator peroxisome proliferator-activated receptor γ coactivator-1α. J Biol Chem 2006; 281: 26540-51.
46. Zhang YK, Yeager RL, Klaassen CD. Circadian expression profiles of drug-processing genes and transcription factors in mouse liver. Drug Metab Dispos 2009; 37: 106-15.
47. Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 2006; 126: 801-10.
48. Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell 2008; 134: 728-42.
49. Takwi AA, Wang YM, Wu J, Michaelis M, Cinatl J, Chen T. miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells. Oncogene 2014; 33: 3717-29.
50. Suino K, Peng L, Reynolds R, Li Y, Cha JY, Repa JJ, et al. The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization. Mol Cell 2004; 16: 893-905.
51. Plevin MJ, Mills MM, Ikura M. The LxxLL motif: a multifunctional binding sequence in transcriptional regulation. Trends Biochem Sci 2005; 30: 66-9.
52. Tzameli I, Pissios P, Schuetz EG, Moore DD. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene is an agonist ligand for the nuclear receptor CAR. Mol Cell Biol 2000; 20: 2951-8.
53. Dussault I, Lin M, Hollister K, Fan M, Termini J, Sherman MA, et al. A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity. Mol Cell Biol 2002; 22: 5270-80.
54. Jyrkkärinne J, Windshügel B, Mäkinen J, Ylisirniö M, Peräkylä M, Poso A, et al. Amino acids important for ligand specificity of the human constitutive androstane receptor. J Biol Chem 2005; 280: 5960-71.
55. Ueda A, Matsui K, Yamamoto Y, Pedersen LC, Sueyoshi T, Negishi M. Thr176 regulates the activity of the mouse nuclear receptor CAR and is conserved in the NR1I subfamily members PXR and VDR. Biochem J 2005; 388: 623-30.
56. Shiraki T, Sakai N, Kanaya E, Jingami H. Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor γ coactivator-1α. A possible link between xenobiotic response and nutritional state. J Biol Chem 2003; 278: 11344-50.
57. Jyrkkärinne J, Mäkinen J, Gynther J, Savolainen H, Poso A, Honkakoski P. Molecular determinants of steroid inhibition for the mouse constitutive androstane receptor. J Med Chem 2003; 46: 4687-95.
58. Xia J, Liao L, Sarkar J, Matsumoto K, Reddy JK, Xu J, et al. Redundant enhancement of mouse constitutive androstane receptor transactivation by p160 coactivator family members. Arch Biochem Biophys 2007; 468: 49-57.
59. Chen T, Chen Q, Xu Y, Zhou Q, Zhu J, Zhang H, et al. SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism. J Hepatol 2012; 56: 210-7.
60. Choi E, Lee S, Yeom SY, Kim GH, Lee JW, Kim SW. Characterization of activating signal cointegrator-2 as a novel transcriptional coactivator of the xenobiotic nuclear receptor constitutive androstane receptor. Mol Endocrinol 2005; 19: 1711-9.
61. Yamamoto Y, Negishi M. The antiapoptotic factor growth arrest and DNA-damage-inducible 45 β regulates the nuclear receptor constitutive active/androstane receptor-mediated transcription. Drug Metab Dispos 2008; 36: 1189-93.
62. Laurenzana EM, Chen T, Kannuswamy M, Sell BE, Strom SC, Li Y, et al. The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3). Mol Pharmacol 2012; 82: 918-28.
63. Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 2000; 14: 121-41.
64. Pascual M, Gómez-Lechón MJ, Castell JV, Jover R. ATF5 is a highly abundant liver-enriched transcription factor that cooperates with constitutive androstane receptor in the transactivation of CYP2B6: implications in hepatic stress responses. Drug Metab Dispos 2008; 36: 1063-72.
65. Ashino T, Ohkubo-Morita H, Yamamoto M, Yoshida T, Numazawa S. Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5. Redox Biology 2014; 2: 284-8.
66. Shizu R, Shindo S, Yoshida T, Numazawa S. Cross-talk between constitutive androstane receptor and hypoxia-inducible factor in the regulation of gene expression. Toxicol Lett 2013; 219: 143-50.
67. Benet M, Lahoz A, Guzmán C, Castell JV, Jover R. CCAAT/enhancerbinding protein α (C/EBPα) and hepatocyte nuclear factor 4α (HNF4α) synergistically cooperate with constitutive androstane receptor to transactivate the human cytochrome P450 2B6 (CYP2B6) gene: application to the development of a metabolically competent human hepatic cell model. J Biol Chem 2010; 285: 28457-71.
68. Aleksunes LM, Klaassen CD. Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-null mice. Drug Metab Dispos 2012; 40: 1366-79.
69. Peng H, Zhu QS, Zhong S, Levy D. Transcription of the human microsomal epoxide hydrolase gene (EPHX1) is regulated by an HNF-4α/CAR/RXR/PSF complex. Biochim Biophys Acta 2013; 1829: 1000-9.
70. Inoue K, Negishi M. Early growth response 1 loops the CYP2B6 promoter for synergistic activation by the distal and proximal nuclear receptors CAR and HNF4α. FEBS Lett 2009; 583: 2126-30.
71. Surapureddi S, Rana R, Reddy JK, Goldstein JA. Nuclear receptor coactivator 6 mediates the synergistic activation of human cytochrome P-450 2C9 by the constitutive androstane receptor and hepatic nuclear factor-4α. Mol Pharmacol 2008; 74: 913-23.
72. Renga B, Migliorati M, Mencarelli A, Cipriani S, D'Amore C, Distrutti E, et al. Farnesoid X receptor suppresses constitutive androstane receptor activity at the multidrug resistance protein-4 promoter. Biochim Biophys Acta 2011; 1809: 157-65.
73. Min G, Kim H, Bae Y, Petz L, Kemper JK. Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR) CAR inhibits ER-mediated signaling pathway by squelching p160 coactivators. J Biol Chem 2002; 277: 34626-33.
74. Takizawa D, Kakizaki S, Horiguchi N, Tojima H, Yamazaki Y, Ichikawa T, et al. Histone deacetylase inhibitors induce cytochrome P450 2B by activating nuclear receptor constitutive androstane receptor. Drug Metab Dispos 2010; 38: 1493-8.
75. Zhai Y, Wada T, Zhang B, Khadem S, Ren S, Kuruba R, et al. A functional cross-talk between liver X receptor-α and constitutive androstane receptor links lipogenesis and xenobiotic responses. Mol Pharmacol 2010; 78: 666-74.
76. Roth A, Looser R, Kaufmann M, Meyer UA. Sterol regulatory element binding protein 1 interacts with pregnane X receptor and constitutive androstane receptor and represses their target genes. Pharmacogenet Genomics 2008; 18: 325-37.
77. Gao J, He J, Zhai Y, Wada T, Xie W. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 2009; 284: 25984-92.
78. Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, et al. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci USA 2009; 106: 18831-6.
79. Roth A, Looser R, Kaufmann M, Blättler SM, Rencurel F, Huang W, et al. Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Mol Pharmacol 2008; 73: 1282-9.
80. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109: 1125-31.
81. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002; 110: 489-500.
82. Falany CN. Enzymology of human cytosolic sulfotransferases. FASEB J 1997; 11: 206-16.
83. Chen W, Chen G, Head DL, Mangelsdorf DJ, Russell DW. Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab 2007; 5: 73-9.
84. Bai Q, Xu L, Kakiyama G, Runge-Morris MA, Hylemon PB, Yin L, et al. Sulfation of 25-hydroxycholesterol by SULT2B1b decreases cellular lipids via the LXR/SREBP-1c signaling pathway in human aortic endothelial cells. Atherosclerosis 2011; 214: 350-6.
85. Shi X, Cheng Q, Xu L, Yan J, Jiang M, He J, et al. Cholesterol sulfate and cholesterol sulfotransferase inhibit gluconeogenesis by targeting hepatocyte nuclear factor 4α. Mol Cell Biol 2014; 34: 485-97.
86. Ma Y, Xu L, Rodriguez-Agudo D, Li X, Heuman DM, Hylemon PB, et al. 25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway. Am J Physiol Endocrinol Metab 2008; 295: E1369-79.
87. Xu L, Shen S, Ma Y, Kim JK, Rodriguez-Agudo D, Heuman DM, et al. 25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages. Am J Physiol Endocrinol Metab 2012; 302: E788-99.
88. Xu L, Kim JK, Bai Q, Zhang X, Kakiyama G, Min HK, et al. 5-Cholesten-3β,25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model. Mol Pharmacol 2013; 83: 648-58.
89. Xu L, Bai Q, Rodriguez-Agudo D, Hylemon PB, Heuman DM, Pandak WM, et al. Regulation of hepatocyte lipid metabolism and inflammatory response by 25-hydroxycholesterol and 25-hydroxycholesterol-3-sulfate. Lipids 2010; 45: 821-32.
90. Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, et al. X-ray structure of the hRORα LBD at 1.63 Å: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα. Structure 2002; 10: 1697-707.
91. Xiao L, Xie X, Zhai Y. Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism. Adv Drug Del Rev 2010; 62: 1316-21.
92. Kodama S, Koike C, Negishi M, Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drugmetabolizing and gluconeogenic enzymes. Mol Cell Biol 2004; 24: 7931-40.
93. Miao J, Fang S, Bae Y, Kemper JK. Functional inhibitory crosstalk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1α. J Biol Chem 2006; 281: 14537-46.
94. Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R, Lewis GF, et al. Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and apob48-containing lipoprotein overproduction. J Biol Chem 2002; 277: 31646-55.
95. Federico LM, Naples M, Taylor D, Adeli K. Intestinal insulin resistance and aberrant production of apolipoprotein b48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine. Diabetes 2006; 55: 1316-26.
96. Masson D, Qatanani M, Sberna AL, Xiao R, de Barros JPP, Grober J, et al. Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice. J Lipid Res 2008; 49: 1682-91.
97. Sberna AL, Assem M, Xiao R, Ayers S, Gautier T, Guiu B, et al. Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice. Atertio Thromb Vasc Biol 2011; 31: 2232-9.
98. Sberna AL, Assem M, Gautier T, Grober J, Guiu B, Jeannin A, et al. Constitutive androstane receptor activation stimulates faecal bile acid excretion and reverse cholesterol transport in mice. J Hepatol 2011; 55: 154-61.
99. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 2001; 21: 1393-403.
100. Tojima H, Kakizaki S, Yamazaki Y, Takizawa D, Horiguchi N, Sato K, et al. Ligand dependent hepatic gene expression profiles of nuclear receptors CAR and PXR. Toxicol Lett 2012; 212: 288-97.
101. Režen T, Tamasi V, Lövgren-Sandblom A, Björkhem I, Meyer UA, Rozman D. Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers. BMC Genomics 2009; 10: 384.
102. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, et al. Role of LXRs in control of lipogenesis. Genes Dev 2000; 14: 2831-8.
103. Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab 2006; 4: 107-10.
104. Horton JD, Shimomura I, Brown MS, Hammer RE, Goldstein JL, Shimano H. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. J Clin Invest 1998; 101: 2331-9.
105. Masuyama H, Hiramatsu Y. Treatment with constitutive androstane receptor ligand during pregnancy prevents insulin resistance in offspring from high-fat diet-induced obese pregnant mice. Am J Physiol Endocrinol Metab 2012; 303: E293-300.
106. Chen WD, Fu X, Dong B, Wang YD, Shiah S, Moore DD, et al. Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver. Hepatology 2012; 56: 1499-508.
107. Slosky LM, Thompson BJ, Sanchez-Covarrubias L, Zhang Y, Laracuente ML, Vanderah TW, et al. Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism. Mol Pharmacol 2013; 84: 774-86.
108. Lemmen J, Tozakidis IE, Bele P, Galla HJ. Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood-brain barrier after CITCO activation. Brain Res 2013; 1501: 68-80.
109. Wang X, Sykes DB, Miller DS. Constitutive androstane receptormediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. Mol Pharmacol 2010; 78: 376-83.
110. Urano T, Usui T, Shiraki M, Ouchi Y, Inoue S. Association of a single nucleotide polymorphism in the constitutive androstane receptor gene with bone mineral density. Geriatr Gerontol Int 2009; 9: 235-41.
111. Cho HY, Jung JY, Park H, Yang JY, Jung S, An JH, et al. In vivo deletion of CAR resulted in high bone mass phenotypes in male mice. J Cell Physiol 2014; 229: 561-71.