Abstract
Background: PXR (Pregnane X Receptor) and CAR (Constitutive Androstane Receptor) are termed as xenobiotic receptors, which are known as core factors in regulation of the transcription of metabolic enzymes and drug transporters. However, accumulating evidence has shown that PXR and CAR exert their effects on energy metabolism through the regulation of gluconeogenesis, lipogenesis and β-oxidation. Therefore, in this review, we are trying to summary recent advances to show how xenobiotic receptors regulate energy metabolism.
Methods: A structured search of databases has been performed by using focused review topics. According to conceptual framework, the main idea of research literature was summarized and presented.
Results: For introduction of each receptor, the general introduction and the critical functions in hepatic glucose and lipid metabolism have been included. Recent important studies have shown that CAR acts as a negative regulator of lipogenesis, gluconeogenesis and β -oxidation. PXR activation induces lipogenesis, inhibits gluconeogenesis and inhabits β-oxidation.
Conclusion: In this review, the importance of xenobiotic receptors in hepatic glucose and lipid metabolism has been confirmed. Therefore, PXR and CAR may become new therapeutic targets for metabolic syndrome, including obesity and diabetes. However, further research is required to promote the clinical application of this new energy metabolism function of xenobiotic receptors.
Keywords: Xenobiotic receptors, Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), Energy metabolism, Glucose metabolism, Lipid metabolism.
Graphical Abstract
[1]
Mukherjee, S.; Mani, S. Orphan nuclear receptors as targets for drug development. Pharm. Res., 2010, 27(8), 1439-1468.
[2]
Forman, B.M.; Evans, R.M. Nuclear hormone receptors activate direct, inverted, and everted repeats. Ann. N. Y. Acad. Sci., 1995, 761, 29-37.
[3]
Billas, I.; Moras, D. Allosteric controls of nuclear receptor function in the regulation of transcription. J. Mol. Biol., 2013, 425(13), 2317-2329.
[4]
Nagy, L.; Schwabe, J.W. Mechanism of the nuclear receptor molecular switch. Trends Biochem. Sci., 2004, 29(6), 317-324.
[5]
Hummasti, S.; Tontonoz, P. Adopting new orphans into the family of metabolic regulators. Mol. Endocrinol., 2008, 22(8), 1743-1753.
[6]
Giguère, V. Orphan nuclear receptors: from gene to function. Endocr. Rev., 1999, 20(5), 689-725.
[7]
Laudet, V. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J. Mol. Endocrinol., 1997, 19(3), 207-226.
[8]
Stanley, L.A.; Horsburgh, B.C.; Ross, J.; Scheer, N.; Wolf, C.R. PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug Metab. Rev., 2006, 38(3), 515-597.
[9]
Guo, P.; Li, Y.; Eslamfam, S.; Ding, W.; Ma, X. Discovery of novel genes mediating glucose and lipid metabolisms. Curr. Protein Pept. Sci., 2017, 18(6), 609-618.
[11]
Kliewer, S.A.; Goodwin, B.; Willson, T.M. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr. Rev., 2002, 23(5), 687-702.
[12]
Kliewer, 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.; Zetterström, R.H.; Perlmann, T.; Lehmann, J.M. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell, 1998, 92(1), 73-82.
[13]
Blumberg, B.; Sabbagh, W., Jr; Juguilon, H.; Bolado, J., Jr; van Meter, C.M.; Ong, E.S.; Evans, R.M. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev., 1998, 12(20), 3195-3205.
[14]
Saradhi, M.; Sengupta, A.; Mukhopadhyay, G.; Tyagi, R.K. Pregnane and Xenobiotic Receptor (PXR/SXR) resides predominantly in the nuclear compartment of the interphase cell and associates with the condensed chromosomes during mitosis. Biochim. Biophys. Acta, 2005, 1746(2), 85-94.
[15]
Kawana, K.; Ikuta, T.; Kobayashi, Y.; Gotoh, O.; Takeda, K.; Kawajiri, K. Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. Mol. Pharmacol., 2003, 63(3), 524-531.
[16]
Squires, E.J.; Sueyoshi, T.; Negishi, M. Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J. Biol. Chem., 2004, 279(47), 49307-49314.
[17]
Wang, H.; LeCluyse, E.L. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin. Pharmacokinet., 2003, 42(15), 1331-1357.
[18]
Lichti-Kaiser, K.; Brobst, D.; Xu, C.; Staudinger, J.L. A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein. J. Pharmacol. Exp. Ther., 2009, 331(1), 65-76.
[19]
Staudinger, J.L.; Xu, C.; Biswas, A.; Mani, S. Post-translational modification of pregnane x receptor. Pharmacol. Res., 2011, 64(1), 4-10.
[20]
Biswas, A.; Pasquel, D.; Tyagi, R.K.; Mani, S. Acetylation of pregnane X receptor protein determines selective function independent of ligand activation. Biochem. Biophys. Res. Commun., 2011, 406(3), 371-376.
[21]
di Masi, A.; De Marinis, E.; Ascenzi, P.; Marino, M. Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects. Mol. Aspects Med., 2009, 30(5), 297-343.
[22]
Smutny, T.; Mani, S.; Pavek, P. Post-translational and post-transcriptional modifications of Pregnane X Receptor (PXR) in regulation of the cytochrome P450 superfamily. Curr. Drug Metab., 2013, 14(10), 1059-1069.
[23]
Venkatesh, M.; Mukherjee, S.; Wang, H.; Li, H.; Sun, K.; Benechet, A.P.; Qiu, Z.; Maher, L.; Redinbo, M.R.; Phillips, R.S.; Fleet, J.C.; Kortagere, S.; Mukherjee, P.; Fasano, A.; Le Ven, J.; Nicholson, J.K.; Dumas, M.E.; Khanna, K.M.; Mani, S. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity, 2014, 41(2), 296-310.
[24]
Jones, S.A.; Moore, L.B.; Shenk, J.L.; Wisely, G.B.; Hamilton, G.A.; McKee, D.D.; Tomkinson, N.C.; LeCluyse, E.L.; Lambert, M.H.; Willson, T.M.; Kliewer, S.A.; Moore, J.T. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol., 2000, 14(1), 27-39.
[25]
Sui, Y.; Ai, N.; Park, S.H.; Rios-Pilier, J.; Perkins, J.T.; Welsh, W.J.; Zhou, C. Bisphenol A and its analogues activate human pregnane X receptor. Environ. Health Perspect., 2012, 120(3), 399-405.
[26]
Zhou, C.; Verma, S.; Blumberg, B. The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nucl. Recept. Signal., 2009, 7, e001.
[27]
Krasowski, M.D.; Ni, A.; Hagey, L.R.; Ekins, S. Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR. Mol. Cell. Endocrinol., 2011, 334(1-2), 39-48.
[28]
Chang, T.K.; Waxman, D.J. Synthetic drugs and natural products as modulators of constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Drug Metab. Rev., 2006, 38(1-2), 51-73.
[29]
Hukkanen, J. Induction of cytochrome P450 enzymes: a view on human in vivo findings. Expert Rev. Clin. Pharmacol., 2012, 5(5), 569-585.
[30]
Rysä, J.; Buler, M.; Savolainen, M.J.; Ruskoaho, H.; Hakkola, J.; Hukkanen, J. Pregnane X receptor agonists impair postprandial glucose tolerance. Clin. Pharmacol. Ther., 2013, 93(6), 556-563.
[31]
Sattar, N.; Taskinen, M.R. Statins are diabetogenic--myth or reality? Atheroscler. Suppl., 2012, 13(1), 1-10.
[32]
Sukhija, R.; Prayaga, S.; Marashdeh, M.; Bursac, Z.; Kakar, P.; Bansal, D.; Sachdeva, R.; Kesan, S.H.; Mehta, J.L. Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients. J. Investig. Med., 2009, 57(3), 495-499.
[33]
Sattar, N.; Preiss, D.; Murray, H.M.; Welsh, P.; Buckley, B.M.; de Craen, A.J.; Seshasai, S.R.; McMurray, J.J.; Freeman, D.J.; Jukema, J.W.; Macfarlane, P.W.; Packard, C.J.; Stott, D.J.; Westendorp, R.G.; Shepherd, J.; Davis, B.R.; Pressel, S.L.; Marchioli, R.; Marfisi, R.M.; Maggioni, A.P.; Tavazzi, L.; Tognoni, G.; Kjekshus, J.; Pedersen, T.R.; Cook, T.J.; Gotto, A.M.; Clearfield, M.B.; Downs, J.R.; Nakamura, H.; Ohashi, Y.; Mizuno, K.; Ray, K.K.; Ford, I. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. Lancet, 2010, 375(9716), 735-742.
[34]
Preiss, D.; Seshasai, S.R.; Welsh, P.; Murphy, S.A.; Ho, J.E.; Waters, D.D.; DeMicco, D.A.; Barter, P.; Cannon, C.P.; Sabatine, M.S.; Braunwald, E.; Kastelein, J.J.; de Lemos, J.A.; Blazing, M.A.; Pedersen, T.R.; Tikkanen, M.J.; Sattar, N.; Ray, K.K. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA, 2011, 305(24), 2556-2564.
[35]
Howe, K.; Sanat, F.; Thumser, A.E.; Coleman, T.; Plant, N. The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes. Xenobiotica, 2011, 41(7), 519-529.
[36]
Carter, A.A.; Gomes, T.; Camacho, X.; Juurlink, D.N.; Shah, B.R.; Mamdani, M.M. Risk of incident diabetes among patients treated with statins: population based study. BMJ, 2013, 346, f2610.
[37]
Zaharan, N.L.; Williams, D.; Bennett, K. Statins and risk of treated incident diabetes in a primary care population. Br. J. Clin. Pharmacol., 2013, 75(4), 1118-1124.
[38]
Puurunen, J.; Piltonen, T.; Puukka, K.; Ruokonen, A.; Savolainen, M.J.; Bloigu, R.; Morin-Papunen, L.; Tapanainen, J.S. Statin therapy worsens insulin sensitivity in women with Polycystic Ovary Syndrome (PCOS): A prospective, randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab., 2013, 98(12), 4798-4807.
[39]
Lahtela, J.T.; Gachalyi, B.; Eksymä, S.; Hämäläinen, A.; Sotaniemi, E.A. The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man. Br. J. Clin. Pharmacol., 1986, 21(1), 19-26.
[40]
Lahtela, J.T.; Särkkä, P.; Sotaniemi, E.A. Phenobarbital treatment enhances insulin mediated glucose metabolism in man. Res. Commun. Chem. Pathol. Pharmacol., 1984, 44(2), 215-226.
[41]
Sotaniemi, E.A.; Arranto, A.J.; Sutinen, S.; Stengård, J.H.; Sutinen, S. Treatment of noninsulin-dependent diabetes mellitus with enzyme inducers. Clin. Pharmacol. Ther., 1983, 33(6), 826-835.
[42]
Lahtela, J.T.; Arranto, A.J.; Sotaniemi, E.A. Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects. Diabetes, 1985, 34(9), 911-916.
[43]
Faucette, S.R.; Zhang, T.C.; Moore, R.; Sueyoshi, T.; Omiecinski, C.J.; LeCluyse, E.L.; Negishi, M.; Wang, H. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J. Pharmacol. Exp. Ther., 2007, 320(1), 72-80.
[44]
Nakamura, K.; Moore, R.; Negishi, M.; Sueyoshi, T. Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J. Biol. Chem., 2007, 282(13), 9768-9776.
[45]
Spruiell, K.; Richardson, R.M.; Cullen, J.M.; Awumey, E.M.; Gonzalez, F.J.; Gyamfi, M.A. Role of pregnane X receptor in obesity and glucose homeostasis in male mice. J. Biol. Chem., 2014, 289(6), 3244-3261.
[46]
Kodama, S.; Moore, R.; Yamamoto, Y.; Negishi, M. Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene. Biochem. J., 2007, 407(3), 373-381.
[47]
Ma, Y.; Liu, D. Activation of pregnane X receptor by pregnenolone 16 α-carbonitrile prevents high-fat diet-induced obesity in AKR/J mice. PLoS One, 2012, 7(6), e38734.
[48]
Zhou, J.; Zhai, Y.; Mu, Y.; Gong, H.; Uppal, H.; Toma, D.; Ren, S.; Evans, R.M.; Xie, W. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J. Biol. Chem., 2006, 281(21), 15013-15020.
[49]
Kodama, S.; Koike, C.; Negishi, M.; Yamamoto, Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol. Cell. Biol., 2004, 24(18), 7931-7940.
[50]
Bhalla, S.; Ozalp, C.; Fang, S.; Xiang, L.; Kemper, J.K. 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., 2004, 279(43), 45139-45147.
[51]
Gotoh, S.; Negishi, M. Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Sci. Rep., 2015, 5, 14076.
[52]
Gotoh, S.; Negishi, M. Serum- and glucocorticoid-regulated kinase 2 determines drug-activated pregnane X receptor to induce gluconeogenesis in human liver cells. J. Pharmacol. Exp. Ther., 2014, 348(1), 131-140.
[53]
Ling, Z.; Shu, N.; Xu, P.; Wang, F.; Zhong, Z.; Sun, B.; Li, F.; Zhang, M.; Zhao, K.; Tang, X.; Wang, Z.; Zhu, L.; Liu, L.; Liu, X. Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. Biochem. Pharmacol., 2016, 100, 98-111.
[54]
Kodama, S.; Negishi, M. PXR cross-talks with internal and external signals in physiological and pathophysiological responses. Drug Metab. Rev., 2013, 45(3), 300-310.
[55]
Bitter, A.; Rümmele, P.; Klein, K.; Kandel, B.A.; Rieger, J.K.; Nüssler, A.K.; Zanger, U.M.; Trauner, M.; Schwab, M.; Burk, O. Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms. Arch. Toxicol., 2015, 89(11), 2089-2103.
[56]
Wakil, S.J.; Abu-Elheiga, L.A. Fatty acid metabolism: target for metabolic syndrome. J. Lipid Res., 2009, 50(Suppl.), S138-S143.
[57]
He, J.; Gao, J.; Xu, M.; Ren, S.; Stefanovic-Racic, M.; O’Doherty, R.M.; Xie, W. PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes, 2013, 62(6), 1876-1887.
[58]
Roth, A.; Looser, R.; Kaufmann, M.; Blättler, S.M.; Rencurel, F.; Huang, W.; Moore, D.D.; Meyer, U.A. Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Mol. Pharmacol., 2008, 73(4), 1282-1289.
[59]
Roth, A.; Looser, R.; Kaufmann, M.; Meyer, U.A. Sterol regulatory element binding protein 1 interacts with pregnane X receptor and constitutive androstane receptor and represses their target genes. Pharmacogenet. Genomics, 2008, 18(4), 325-337.
[60]
Reue, K.; Zhang, P. The lipin protein family: dual roles in lipid biosynthesis and gene expression. FEBS Lett., 2008, 582(1), 90-96.
[61]
Peterson, T.R.; Sengupta, S.S.; Harris, T.E.; Carmack, A.E.; Kang, S.A.; Balderas, E.; Guertin, D.A.; Madden, K.L.; Carpenter, A.E.; Finck, B.N.; Sabatini, D.M. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell, 2011, 146(3), 408-420.
[62]
Moreau, A.; Téruel, C.; Beylot, M.; Albalea, V.; Tamasi, V.; Umbdenstock, T.; Parmentier, Y.; Sa-Cunha, A.; Suc, B.; Fabre, J.M.; Navarro, F.; Ramos, J.; Meyer, U.; Maurel, P.; Vilarem, M.J.; Pascussi, J.M. A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte. Hepatology, 2009, 49(6), 2068-2079.
[63]
Aipoalani, D.L.; O’Callaghan, B.L.; Mashek, D.G.; Mariash, C.N.; Towle, H.C. Overlapping roles of the glucose-responsive genes, S14 and S14R, in hepatic lipogenesis. Endocrinology, 2010, 151(5), 2071-2077.
[64]
Kinlaw, W.B.; Church, J.L.; Harmon, J.; Mariash, C.N. Direct evidence for a role of the “spot 14” protein in the regulation of lipid synthesis. J. Biol. Chem., 1995, 270(28), 16615-16618.
[65]
Guillou, H.; Zadravec, D.; Martin, P.G.; Jacobsson, A. The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice. Prog. Lipid Res., 2010, 49(2), 186-199.
[66]
Pawlak, M.; Lefebvre, P.; Staels, B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J. Hepatol., 2015, 62(3), 720-733.
[67]
George, J.; Liddle, C. Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets. Mol. Pharm., 2008, 5(1), 49-59.
[68]
Baes, M.; Gulick, T.; Choi, H.S.; Martinoli, M.G.; Simha, D.; Moore, D.D. A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol. Cell. Biol., 1994, 14(3), 1544-1552.
[69]
Choi, H.S.; Chung, M.; Tzameli, I.; Simha, D.; Lee, Y.K.; Seol, W.; Moore, D.D. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J. Biol. Chem., 1997, 272(38), 23565-23571.
[70]
Forman, B.M.; Tzameli, I.; Choi, H.S.; Chen, J.; Simha, D.; Seol, W.; Evans, R.M.; Moore, D.D. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature, 1998, 395(6702), 612-615.
[71]
Yoshinari, K.; Sueyoshi, T.; Moore, R.; Negishi, M. Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYB2B1 gene by phenobarbital in rat livers. Mol. Pharmacol., 2001, 59(2), 278-284.
[72]
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(5), 1069-1075.
[73]
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(1-3), 17-20.
[74]
Timsit, Y.E.; Negishi, M. Coordinated regulation of nuclear receptor CAR by CCRP/DNAJC7, HSP70 and the ubiquitin-proteasome system. PLoS One, 2014, 9(5), e96092.
[75]
Li, H.; Chen, T.; Cottrell, J.; Wang, H. Nuclear translocation of adenoviral-enhanced yellow fluorescent protein-tagged-human constitutive androstane receptor (hCAR): a novel tool for screening hCAR activators in human primary hepatocytes. Drug Metab. Dispos., 2009, 37(5), 1098-1106.
[76]
Jacobs, M.N.; Dickins, M.; Lewis, D.F. Homology modelling of the nuclear receptors: human oestrogen receptorbeta (hERbeta), the human pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor alpha (hERalpha) crystal structure, and the human peroxisome proliferator activated receptor alpha (PPARalpha) ligand binding domain from the human PPARgamma crystal structure. J. Steroid Biochem. Mol. Biol., 2003, 84(2-3), 117-132.
[77]
Maglich, J.M.; Parks, D.J.; Moore, L.B.; Collins, J.L.; Goodwin, B.; Billin, A.N.; Stoltz, C.A.; Kliewer, S.A.; Lambert, M.H.; Willson, T.M.; Moore, J.T. Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J. Biol. Chem., 2003, 278(19), 17277-17283.
[78]
Tzameli, I.; Pissios, P.; Schuetz, E.G.; Moore, D.D. 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(9), 2951-2958.
[79]
Moore, L.B.; Parks, D.J.; Jones, S.A.; Bledsoe, R.K.; Consler, T.G.; Stimmel, J.B.; Goodwin, B.; Liddle, C.; Blanchard, S.G.; Willson, T.M.; Collins, J.L.; Kliewer, S.A. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem., 2000, 275(20), 15122-15127.
[80]
Dong, B.; Saha, P.K.; Huang, W.; Chen, W.; Abu-Elheiga, L.A.; Wakil, S.J.; Stevens, R.D.; Ilkayeva, O.; Newgard, C.B.; Chan, L.; Moore, D.D. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc. Natl. Acad. Sci. USA, 2009, 106(44), 18831-18836.
[81]
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(38), 25984-25992.
[82]
Manenti, G.; Dragani, T.A.; Della Porta, G. Effects of phenobarbital and 1,4-bis [2-(3,5-dichloropyridyloxy)]benzene on differentiated functions in mouse liver. Chem. Biol. Interact., 1987, 64(1-2), 83-92.
[83]
Argaud, D.; Halimi, S.; Catelloni, F.; Leverve, X.M. Inhibition of gluconeogenesis in isolated rat hepatocytes after chronic treatment with phenobarbital. Biochem. J., 1991, 280(Pt 3), 663-669.
[84]
Miao, J.; Fang, S.; Bae, Y.; Kemper, J.K. 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., 2006, 281(21), 14537-14546.
[85]
Gao, J.; Yan, J.; Xu, M.; Ren, S.; Xie, W. CAR Suppresses Hepatic Gluconeogenesis by Facilitating the Ubiquitination and Degradation of PGC1α. Mol. Endocrinol., 2015, 29(11), 1558-1570.
[86]
Shi, X.; Cheng, Q.; Xu, L.; Yan, J.; Jiang, M.; He, J.; Xu, M.; Stefanovic-Racic, M.; Sipula, I.; O’Doherty, R.M.; Ren, S.; Xie, W. Cholesterol sulfate and cholesterol sulfotransferase inhibit gluconeogenesis by targeting hepatocyte nuclear factor 4α. Mol. Cell. Biol., 2014, 34(3), 485-497.
[87]
Marmugi, A.; Lukowicz, C.; Lasserre, F.; Montagner, A.; Polizzi, A.; Ducheix, S.; Goron, A.; Gamet-Payrastre, L.; Gerbal-Chaloin, S.; Pascussi, J.M.; Moldes, M.; Pineau, T.; Guillou, H.; Mselli-Lakhal, L. Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way. Toxicol. Appl. Pharmacol., 2016, 303, 90-100.
[88]
Yarushkin, A.A.; Kazantseva, Y.A.; Prokopyeva, E.A.; Markova, D.N.; Pustylnyak, Y.A.; Pustylnyak, V.O. Constitutive androstane receptor activation evokes the expression of glycolytic genes. Biochem. Biophys. Res. Commun., 2016, 478(3), 1099-1105.
[89]
Valera, A.; Pujol, A.; Gregori, X.; Riu, E.; Visa, J.; Bosch, F. Evidence from transgenic mice that myc regulates hepatic glycolysis. FASEB J., 1995, 9(11), 1067-1078.
[90]
Masuyama, H.; Hiramatsu, Y. Treatment with a constitutive androstane receptor ligand ameliorates the signs of preeclampsia in high-fat diet-induced obese pregnant mice. Mol. Cell. Endocrinol., 2012, 348(1), 120-127.
[91]
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(2), E293-E300.
[92]
Horton, J.D.; Goldstein, J.L.; Brown, M.S.J. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest., 2002, 109(9), 1125-1131.
[93]
Zhai, Y.; Wada, T.; Zhang, B.; Khadem, S.; Ren, S.; Kuruba, R.; Li, S.; Xie, W. A functional cross-talk between liver X receptor-α and constitutive androstane receptor links lipogenesis and xenobiotic responses. Mol. Pharmacol., 2010, 78(4), 666-674.
[94]
Chen, W.; Chen, G.; Head, D.L.; Mangelsdorf, D.J.; Russell, D.W. Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab., 2007, 5(1), 73-79.
[95]
Xiao, L.; Xie, X.; Zhai, Y. Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism. Adv. Drug Deliv. Rev., 2010, 62(13), 1316-1321.
[96]
Maglich, J.M.; Lobe, D.C.; Moore, J.T. The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress. J. Lipid Res., 2009, 50(3), 439-445.
[97]
Breuker, C.; Moreau, A.; Lakhal, L.; Tamasi, V.; Parmentier, Y.; Meyer, U.; Maurel, P.; Lumbroso, S.; Vilarem, M.J.; Pascussi, J.M. Hepatic expression of thyroid hormone-responsive spot 14 protein is regulated by constitutive androstane receptor (NR1I3). Endocrinology, 2010, 151(4), 1653-1661.
[98]
Kassam, A.; Winrow, C.J.; Fernandez-Rachubinski, F.; Capone, J.P.; Rachubinski, R.A. The peroxisome proliferator response element of the gene encoding the peroxisomal beta-oxidation enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase is a target for constitutive androstane receptor beta/9-cis-retinoic acid receptor-mediated transactivation. J. Biol. Chem., 2000, 275(6), 4345-4350.
[99]
Lynch, C.; Pan, Y.; Li, L.; Heyward, S.; Moeller, T.; Swaan, P.W.; Wang, H. Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes. Toxicol. Appl. Pharmacol., 2014, 279(1), 33-42.
Related Books
Localized Micro/Nanocarriers for Programmed and On-Demand Controlled Drug Release
Mixed Polymeric Micelles for Osteosarcoma Therapy: Development and Characterization
A Comprehensive Text Book on Self-emulsifying Drug Delivery Systems
Nanomaterials: Evolution and Advancement towards Therapeutic Drug Delivery (Part II)
Nanomaterials: Evolution and Advancement Towards Therapeutic Drug Delivery (Part I)
Article Metrics
43
2