The xenobiotic receptors PXR and CAR in liver physiology, an update

Xinran Cai1, Gregory M. Young1, Wen Xie1,2
1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA

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Wang, 2012, Role of CAR and PXR in xenobiotic sensing and metabolism, Expert Opin. Drug Metab. Toxicol., 8, 803, 10.1517/17425255.2012.685237

Chai, 2013, Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond, Expert Opin. Drug Metab. Toxicol., 9, 253, 10.1517/17425255.2013.754010

Kakizaki, 2011, Nuclear receptors CAR and PXR; therapeutic targets for cholestatic liver disease, Front Biosci (Landmark Ed), 16, 2988, 10.2741/3893

Gao, 2012, Targeting xenobiotic receptors PXR and CAR for metabolic diseases, Trends Pharmacol. Sci., 33, 552, 10.1016/j.tips.2012.07.003

Yoshinari, 2019, Role of nuclear receptors PXR and CAR in xenobiotic-induced hepatocyte proliferation and chemical carcinogenesis, Biol. Pharm. Bull., 42, 1243, 10.1248/bpb.b19-00267

Watkins, 2001, The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity, Science, 292, 2329, 10.1126/science.1060762

Moore, 2003, Functional and structural comparison of PXR and CAR, Biochim. Biophys. Acta, 1619, 235, 10.1016/S0304-4165(02)00481-6

Xie, 2000, Humanized xenobiotic response in mice expressing nuclear receptor SXR, Nature, 406, 435, 10.1038/35019116

Kliewer, 1998, An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway, Cell, 92, 73, 10.1016/S0092-8674(00)80900-9

Nebert, 1987, P450 genes: structure, evolution, and regulation, Annu. Rev. Biochem., 56, 945, 10.1146/annurev.bi.56.070187.004501

Kast, 2002, Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor, J. Biol. Chem., 277, 2908, 10.1074/jbc.M109326200

Geick, 2001, Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin, J. Biol. Chem., 276, 14581, 10.1074/jbc.M010173200

Synold, 2001, The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux, Nat. Med., 7, 584, 10.1038/87912

Pavek, 2016, Pregnane X receptor (PXR)-mediated gene repression and cross-talk of PXR with other nuclear receptors via coactivator interactions, Front. Pharmacol., 7, 456, 10.3389/fphar.2016.00456

Moore, 2000, Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands, J. Biol. Chem., 275, 15122, 10.1074/jbc.M001215200

Tzameli, 2000, The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR, Mol. Cell. Biol., 20, 2951, 10.1128/MCB.20.9.2951-2958.2000

Honkakoski, 1998, The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene, Mol. Cell. Biol., 18, 5652, 10.1128/MCB.18.10.5652

Kawamoto, 1999, Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene, Mol. Cell. Biol., 19, 6318, 10.1128/MCB.19.9.6318

Guo, 2006, 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., 347, 485, 10.1016/j.bbrc.2006.06.129

Hosseinpour, 2006, Serine 202 regulates the nuclear translocation of constitutive active/androstane receptor, Mol. Pharmacol., 69, 1095, 10.1124/mol.105.019505

Mutoh, 2009, Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3), J. Biol. Chem., 284, 34785, 10.1074/jbc.M109.048108

Kodama, 2007, Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene, Biochem. J., 407, 373, 10.1042/BJ20070481

Kodama, 2004, Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes, Mol. Cell. Biol., 24, 7931, 10.1128/MCB.24.18.7931-7940.2004

Zhou, 2006, A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway, J. Biol. Chem., 281, 15013, 10.1074/jbc.M511116200

Hassani-Nezhad-Gashti, 2018, Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver, Biochem. Pharmacol., 148, 253, 10.1016/j.bcp.2018.01.001

Nakamura, 2007, Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver, J. Biol. Chem., 282, 9768, 10.1074/jbc.M610072200

Zhao, 2017, Pregnane X receptor (PXR) deficiency improves high fat diet-induced obesity via induction of fibroblast growth factor 15 (FGF15) expression, Biochem. Pharmacol., 142, 194, 10.1016/j.bcp.2017.07.019

Spruiell, 2014, Role of pregnane X receptor in obesity and glucose homeostasis in male mice, J. Biol. Chem., 289, 3244, 10.1074/jbc.M113.494575

He, 2013, PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice, Diabetes, 62, 1876, 10.2337/db12-1039

Kwong, 2019, Sphingosine-1-phosphate signaling and the gut-liver axis in liver diseases, Liver Res, 3, 19, 10.1016/j.livres.2019.02.003

McLean, 2012, Cholesterol, an essential molecule: diverse roles involving cytochrome P450 enzymes, Biochem. Soc. Trans., 40, 587, 10.1042/BST20120077

Xie, 2001, An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids, Proc. Natl. Acad. Sci. U. S. A., 98, 3375, 10.1073/pnas.051014398

Teng, 2007, Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis, Br. J. Pharmacol., 151, 367, 10.1038/sj.bjp.0707235

Kadakol, 2000, Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype, Hum. Mutat., 16, 297, 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z

Xie, 2003, Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor, Proc. Natl. Acad. Sci. U. S. A., 100, 4150, 10.1073/pnas.0438010100

Thatcher, 1994, Origins of hepatomegaly produced by dexamethasone (DEX), pregnenolone 16 alpha-carbonitrile (PCN) and phenobarbitone (PB) in female Sprague-Dawley rats, Biochem. Soc. Trans., 22, 132S, 10.1042/bst022132s

Staudinger, 2001, Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor, Drug Metab. Dispos., 29, 1467

Shizu, 2013, Cross-talk between constitutive androstane receptor and hypoxia-inducible factor in the regulation of gene expression, Toxicol. Lett., 219, 143, 10.1016/j.toxlet.2013.03.014

Kodama, 2011, Pregnane X receptor PXR activates the GADD45beta gene, eliciting the p38 MAPK signal and cell migration, J. Biol. Chem., 286, 3570, 10.1074/jbc.M110.179812

Jiang, 2019, Pregnane X receptor regulates liver size and liver cell fate by yes-associated protein activation in mice, Hepatology, 69, 343, 10.1002/hep.30131

Dai, 2008, Pregnane X receptor is essential for normal progression of liver regeneration, Hepatology, 47, 1277, 10.1002/hep.22129

Haines, 2018, Comparison of the effects of sodium phenobarbital in wild type and humanized constitutive androstane receptor (CAR)/pregnane X receptor (PXR) mice and in cultured mouse, rat and human hepatocytes, Toxicology, 396-397, 23, 10.1016/j.tox.2018.02.001

H.K. Seitz, R. Bataller, H. Cortez-Pinto, B. Gao, A. Gual, C. Lackner, P. Mathurin, S. Mueller, G. Szabo, H. Tsukamoto, Alcoholic liver disease, Nat Rev Dis Primers, 4 (2018) 16.

Choi, 2018, Role of the pregnane X receptor in binge ethanol-induced steatosis and hepatotoxicity, J. Pharmacol. Exp. Ther., 365, 165, 10.1124/jpet.117.244665

Choi, 2018, Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice, J. Biol. Chem., 293, 1, 10.1074/jbc.M117.815217

Xie, 2019, Activation of pregnane X receptor sensitizes mice to hemorrhagic shock-induced liver injury, Hepatology, 70, 995, 10.1002/hep.30691

Kodama, 2004, Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes, Mol. Cell. Biol., 24, 7931, 10.1128/MCB.24.18.7931-7940.2004

Miao, 2006, Functional inhibitory cross-talk 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-1alpha, J. Biol. Chem., 281, 14537, 10.1074/jbc.M510713200

Gao, 2015, CAR suppresses hepatic gluconeogenesis by facilitating the ubiquitination and degradation of PGC1alpha, Mol. Endocrinol., 29, 1558, 10.1210/me.2015-1145

Marmugi, 2016, Activation of the constitutive androstane receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way, Toxicol. Appl. Pharmacol., 303, 90, 10.1016/j.taap.2016.05.006

Choi, 2018, Activation of constitutive androstane receptor ameliorates renal ischemia-reperfusion-induced kidney and liver injury, Mol. Pharmacol., 93, 239, 10.1124/mol.117.111146

Cheng, 2017, Activation of constitutive androstane receptor prevents cholesterol gallstone formation, Am. J. Pathol., 187, 808, 10.1016/j.ajpath.2016.12.013

Lukowicz, 2019, Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor, Sci. Rep., 9, 20169, 10.1038/s41598-019-56570-0

Gao, 2009, The constitutive androstane receptor is an anti-obesity nuclear receptor that improves in sulin sensitivity, J. Biol. Chem., 284, 25984, 10.1074/jbc.M109.016808

Dong, 2009, Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease, Proc. Natl. Acad. Sci. U. S. A., 106, 18831, 10.1073/pnas.0909731106

Tian, 2011, Gadd45beta is an inducible coactivator of transcription that facilitates rapid liver growth in mice, J. Clin. Invest., 121, 4491, 10.1172/JCI38760

Cai, 2020, Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR), Acta Pharm. Sin. B, 11, 434, 10.1016/j.apsb.2020.08.015

Huang, 2003, Induction of bilirubin clearance by the constitutive androstane receptor (CAR), Proc. Natl. Acad. Sci. U. S. A., 100, 4156, 10.1073/pnas.0630614100

Catz, 1962, Pharmacological modification of bilirubin conjugation in newborn, in, American Journal of Diseases of Children, 104, 516

Yaffe, 1966, Enhancement of glucuronide-conjugating capacity in a hyperbilirubinemic infant due to apparent enzyme induction by phenobarbital, N. Engl. J. Med., 275, 1461, 10.1056/NEJM196612292752602

Saini, 2004, A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification, Mol. Pharmacol., 65, 292, 10.1124/mol.65.2.292

Kim, 2019, Constitutive androstane receptor differentially regulates bile acid homeostasis in mouse models of intrahepatic cholestasis, Hepatol Commun, 3, 147, 10.1002/hep4.1274

Lickteig, 2019, Effects of absence of constitutive androstane receptor (CAR) on bile acid homeostasis in male and female mice, Toxicol Sci, 171, 132, 10.1093/toxsci/kfz143

Columbano, 2005, Gadd45β is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia, Hepatology, 42, 1118, 10.1002/hep.20883

Chen, 2012, SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism, J. Hepatol., 56, 210, 10.1016/j.jhep.2011.07.015

Kettner, 2016, Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis, Cancer Cell, 30, 909, 10.1016/j.ccell.2016.10.007

Tschuor, 2016, Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss, J. Hepatol., 65, 66, 10.1016/j.jhep.2016.02.040

Bhushan, 2019, TCPOBOP-induced hepatomegaly and hepatocyte proliferation are attenuated by combined disruption of MET and EGFR signaling, Hepatology, 69, 1702, 10.1002/hep.30109

Bhushan, 2020, Yap is crucial for CAR-driven hepatocyte proliferation, but not for induction of drug metabolism genes in mice, Hepatology

Abe, 2018, Role of YAP activation in nuclear receptor CAR-mediated proliferation of mouse hepatocytes, Toxicol. Sci., 165, 408, 10.1093/toxsci/kfy149

Soldatow, 2016, Development of an in vitro high content imaging assay for quantitative assessment of CAR-dependent mouse, rat, and human primary hepatocyte proliferation, Toxicol. in Vitro, 36, 224, 10.1016/j.tiv.2016.08.006

Chen, 2011, The nuclear receptor CAR modulates alcohol-induced liver injury, Lab. Investig., 91, 1136, 10.1038/labinvest.2011.68

Ludwig, 1980, Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease, Mayo Clin. Proc., 55, 434

Yamazaki, 2007, The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis, Gut, 56, 565, 10.1136/gut.2006.093260

Rewa, 2014, Acute kidney injury-epidemiology, outcomes and economics, Nat Rev Nephrol, 10, 193, 10.1038/nrneph.2013.282

Targher, 2017, Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease, Nat Rev Nephrol, 13, 297, 10.1038/nrneph.2017.16

Honkakoski, 2003, Drug-activated nuclear receptors CAR and PXR, Ann. Med., 35, 172, 10.1080/07853890310008224

Xie, 2000, Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR, Genes Dev., 14, 3014, 10.1101/gad.846800

Li, 2013, Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy, Nat. Med., 19, 418, 10.1038/nm.3104

Yu, 2020, Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI, Sci. Transl. Med., 12, 10.1126/scitranslmed.aay7591

Cho, 2011, Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants, Clin. Pharmacol. Ther., 89, 416, 10.1038/clpt.2010.266

Bhalla, 2004, Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism, J. Biol. Chem., 279, 45139, 10.1074/jbc.M405423200

Gotoh, 2015, Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis, Sci. Rep., 5, 10.1038/srep14076

Kachaylo, 2012, Constitutive androstane receptor activation by 2,4,6-triphenyldioxane-1,3 suppresses the expression of the gluconeogenic genes, Eur. J. Pharmacol., 679, 139, 10.1016/j.ejphar.2012.01.007

Bitter, 2015, Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms, Arch. Toxicol., 89, 2089, 10.1007/s00204-014-1348-x

Li, 2015, SLC13A5 is a novel transcriptional target of the pregnane X receptor and sensitizes drug-induced steatosis in human liver, Mol. Pharmacol., 87, 674, 10.1124/mol.114.097287

Roth, 2008, Sterol regulatory element binding protein 1 interacts with pregnane X receptor and constitutive androstane receptor and represses their target genes, Pharmacogenet. Genomics, 18, 325, 10.1097/FPC.0b013e3282f706e0

Zhai, 2010, A functional cross-talk between liver X receptor-α and constitutive androstane receptor links lipogenesis and xenobiotic responses, Mol. Pharmacol., 78, 666, 10.1124/mol.110.064618

Roth, 2008, Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression, Mol. Pharmacol., 73, 1282, 10.1124/mol.107.041012

Zhou, 2008, Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis, Gastroenterology, 134, 556, 10.1053/j.gastro.2007.11.037

Yarushkin, 2016, Constitutive androstane receptor activation evokes the expression of glycolytic genes, Biochem. Biophys. Res. Commun., 478, 1099, 10.1016/j.bbrc.2016.08.075

Staudinger, 2001, The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity, Proc. Natl. Acad. Sci. U. S. A., 98, 3369, 10.1073/pnas.051551698

He, 2011, PXR prevents cholesterol gallstone disease by regulating biosynthesis and transport of bile salts, Gastroenterology, 140, 2095, 10.1053/j.gastro.2011.02.055

Lickteig, 2016, Activation of constitutive androstane receptor (CAR) in mice results in maintained biliary excretion of bile acids despite a marked decrease of bile acids in liver, Toxicol Sci, 151, 403, 10.1093/toxsci/kfw054

Zhang, 2004, The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity, J. Biol. Chem., 279, 49517, 10.1074/jbc.M409041200

Wagner, 2005, CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice, Hepatology, 42, 420, 10.1002/hep.20784

Teng, 2003, Induction of ABCC3 (MRP3) by pregnane X receptor activators, Drug Metab. Dispos., 31, 1296, 10.1124/dmd.31.11.1296

Kowalik, 2011, Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice, Hepatology, 53, 2086, 10.1002/hep.24289

Hori, 2018, Nuclear receptor CAR suppresses GADD45B-p38 MAPK signaling to promote phenobarbital-induced proliferation in mouse liver, Mol. Cancer Res., 16, 1309, 10.1158/1541-7786.MCR-18-0118

W.E. Blanco-Bose, M.J. Murphy, A. Ehninger, S. Offner, C. Dubey, W. Huang, D.D. Moore, A. Trumpp, c-Myc and its target foxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia, Hepatology, 48 (2008) 1302–1311.

Kazantseva, 2015, Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver, Toxicol. Appl. Pharmacol., 288, 26, 10.1016/j.taap.2015.07.004

Huang, 2005, Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor, Mol. Endocrinol., 19, 1646, 10.1210/me.2004-0520