孕烷X受体在内源物质代谢中的功能
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摘要
核受体(nuclear receptor, NR)超家族成员孕烷X受体(pregnane X receptor, PXR)是一个配体激活型转录因子,高表达于肝脏和肠组织,在其它某些组织器官中也存在表达。PXR与维甲酸X受体(retinoid X receptor, RXR)形成异源二聚体,在招募大量共活化因子后,与特异性DNA响应元件结合发挥转录调控功能。PXR是一个公认的外源物质感受器,因此,PXR最初被认为是一种调节药物代谢酶和转运体的NR。但目前已知PXR也是同等重要的内源物质受体。最近的研究显示PXR激活可以调节体内葡萄糖代谢、脂质代谢、类固醇内分泌稳态、胆酸和胆红素去毒化、骨矿物质平衡和免疫炎症反应等,本文就这几个方面对PXR作一个综述。
As a member of the nuclear receptor superfamily, the pregnane X receptor(PXR) is a ligand-activated transcription factor. PXR is highly expressed in liver and intestinal tissues, and also found in other tissues and organs, such as stomach and kidney. After heterodimerization with retinoid X receptor(RXR), PXR recruits numerous co-activating factors, and binds to specific DNA response elements to perform transcriptional regulation of the downstream target genes. As an acknowledged receptor for xenobiotics, PXR was initially considered as a nuclear receptor regulating drug metabolizing enzymes and transporters. However, nowadays, PXR has also been recognized as an important endobiotic receptor. Recent studies have shown that PXR activation can regulate glucose metabolism, lipid metabolism, steroid endocrine homeostasis, detoxification of cholic acid and bilirubin, bone mineral balance, and immune inflammation in vivo. This review focuses on the role of PXR in metabolism of endogenous substances.
As a member of the nuclear receptor superfamily, the pregnane X receptor(PXR) is a ligand-activated transcription factor. PXR is highly expressed in liver and intestinal tissues, and also found in other tissues and organs, such as stomach and kidney. After heterodimerization with retinoid X receptor(RXR), PXR recruits numerous co-activating factors, and binds to specific DNA response elements to perform transcriptional regulation of the downstream target genes. As an acknowledged receptor for xenobiotics, PXR was initially considered as a nuclear receptor regulating drug metabolizing enzymes and transporters. However, nowadays, PXR has also been recognized as an important endobiotic receptor. Recent studies have shown that PXR activation can regulate glucose metabolism, lipid metabolism, steroid endocrine homeostasis, detoxification of cholic acid and bilirubin, bone mineral balance, and immune inflammation in vivo. This review focuses on the role of PXR in metabolism of endogenous substances.
引文
1 Kliewer SA,Moore JT,Wade L,Staudinger JL,Watson MA,Jones SA,McKee DD,Oliver BB,Willson TM,Zetterstrom RH,Perlmann T,Lehmann JM.An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway.Cell 1998;92(1):73-82.
2 Orans J,Teotico DG,Redinbo MR.The nuclear xenobiotic receptor pregnane X receptor:recent insights and new challenges.Mol Endocrinol 2005;19(12):2891-2900.
3 Zhang B,Xie W,Krasowski MD.PXR:a xenobiotic receptor of diverse function implicated in pharmacogenetics.Pharmacogenomics 2008;9(11):1695-1709.
4 Umesono K,Evans RM.Determinants of target gene specificity for steroid/thyroid hormone receptors.Cell 1989;57(7):1139-1146.
5 Mangelsdorf DJ,Evans RM.The RXR heterodimers and orphan receptors.Cell 1995;83(6):841-850.
6 Bhalla S,Ozalp C,Fang S,Xiang L,Kemper JK.Ligandactivated 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.
7 Kodama S,Moore R,Yamamoto Y,Negishi M.Human nuclear pregnane X receptor cross-talk with CREB to repress c AMP activation of the glucose-6-phosphatase gene.Biochem J 2007;407(3):373-381.
8 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.
9 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.
10 Zhou J,Zhai Y,Mu Y,Gong H,Uppal H,Toma D,Ren S,Evans RM,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.
11 Gotoh S,Negishi M.Statin-activated nuclear receptor PXRpromotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.Sci Rep 2015;5:14076.
12 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.
13 Rysa J,Buler M,Savolainen MJ,Ruskoaho H,Hakkola J,Hukkanen J.Pregnane X receptor agonists impair postprandial glucose tolerance.Clin Pharmacol Ther 2013;93(6):556-563.
14 Matschinsky FM.GKAs for diabetes therapy:why no clinically useful drug after two decades of trying?Trends Pharmacol Sci 2013;34(2):90-99.
15 Postic C,Shiota M,Niswender KD,Jetton TL,Chen Y,Moates JM,Shelton KD,Lindner J,Cherrington AD,Magnuson MA.Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.J Biol Chem 1999;274(1):305-315.
16 Burcelin R,del Carmen Munoz M,Guillam MT,Thorens B.Liver hyperplasia and paradoxical regulation of glycogen metabolism and glucose-sensitive gene expression in GLUT2-null hepatocytes.Further evidence for the existence of a membrane-based glucose release pathway.J Biol Chem2000;275(15):10930-10936.
17 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.
18 Yoshikawa T,Shimano H,Amemiya-Kudo M,Yahagi N,Hasty AH,Matsuzaka T,Okazaki H,Tamura Y,Iizuka Y,Ohashi K,Osuga J,Harada K,Gotoda T,Kimura S,Ishibashi S,Yamada N.Identification of liver X receptor-retinoid Xreceptor as an activator of the sterol regulatory elementbinding protein 1c gene promoter.Mol Cell Biol 2001;21(9):2991-3000.
19 Misawa K,Horiba T,Arimura N,Hirano Y,Inoue J,Emoto N,Shimano H,Shimizu M,Sato R.Sterol regulatory elementbinding protein-2 interacts with hepatocyte nuclear factor-4to enhance sterol isomerase gene expression in hepatocytes.J Biol Chem 2003;278(38):36176-36182.
20 Kanayama T,Arito M,So K,Hachimura S,Inoue J,Sato R.Interaction between sterol regulatory element-binding proteins and liver receptor homolog-1 reciprocally suppresses their transcriptional activities.J Biol Chem 2007;282(14):10290-10298.
21 Febbraio M,Silverstein RL.CD36:implications in cardiovascular disease.Int J Biochem Cell Biol 2007;39(11):2012-2030.
22 Zhou J,Febbraio M,Wada T,Zhai Y,Kuruba R,He J,Lee JH,Khadem S,Ren S,Li S,Silverstein RL,Xie W.Hepatic fatty acid transporter Cd36 is a common target of LXR,PXR,and PPARgamma in promoting steatosis.Gastroenterology 2008;134(2):556-567.
23 Wolfrum C,Asilmaz E,Luca E,Friedman JM,Stoffel M.Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes.Nature 2004;432(7020):1027-1032.
24 Li T,Chen W,Chiang JY.PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine.J Lipid Res2007;48(2):373-384.
25 Masson D,Lagrost L,Athias A,Gambert P,Brimer-Cline C,Lan L,Schuetz JD,Schuetz EG,Assem M.Expression of the pregnane X receptor in mice antagonizes the cholic acidmediated changes in plasma lipoprotein profile.Arterioscler Thromb Vasc Biol 2005;25(10):2164-2169.
26 Sporstol M,Tapia G,Malerod L,Mousavi SA,Berg T.Pregnane X receptor-agonists down-regulate hepatic ATP-binding cassette transporter A1 and scavenger receptor class B type I.Biochem Biophys Res Commun 2005;331(4):1533-1541.
27 Strott CA.Sulfonation and molecular action.Endocr Rev2002;23(5):703-732.
28 Zhang B,Cheng Q,Ou Z,Lee JH,Xu M,Kochhar U,Ren S,Huang M,Pflug BR,Xie W.Pregnane X receptor as a therapeutic target to inhibit androgen activity.Endocrinology2010;151(12):5721-5729.
29 Zhai Y,Pai HV,Zhou J,Amico JA,Vollmer RR,Xie W.Activation of pregnane X receptor disrupts glucocorticoid and mineralocorticoid homeostasis.Mol Endocrinol 2007;21(1):138-147.
30 Sui Y,Helsley RN,Park SH,Song X,Liu Z,Zhou C.Intestinal pregnane X receptor links xenobiotic exposure and hypercholesterolemia.Mol Endocrinol 2015;29(5):765-776.
31 Fiorucci S,Rizzo G,Donini A,Distrutti E,Santucci L.Targeting farnesoid X receptor for liver and metabolic disorders.Trends Mol Med 2007;13(7):298-309.
32 Xie W,Radominska-Pandya A,Shi Y,Simon CM,Nelson MC,Ong ES,Waxman DJ,Evans RM.An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.Proc Natl Acad Sci U S A 2001;98(6):3375-3380.
33 Sonoda J,Xie W,Rosenfeld JM,Barwick JL,Guzelian PS,Evans RM.Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor(PXR).Proc Natl Acad Sci U S A 2002;99(21):13801-13806.
34 Staudinger JL,Goodwin B,Jones SA,Hawkins-Brown D,MacKenzie KI,LaTour A,Liu Y,Klaassen CD,Brown KK,Reinhard J,Willson TM,Koller BH,Kliewer SA.The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc Natl Acad Sci U S A 2001;98(6):3369-3374.
35 Kast HR,Goodwin B,Tarr PT,Jones SA,Anisfeld AM,Stoltz CM,Tontonoz P,Kliewer S,Willson TM,Edwards PA.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 2002;277(4):2908-2915.
36 Frank C,Makkonen H,Dunlop TW,Matilainen M,Vaisanen S,Carlberg C.Identification of pregnane X receptor binding sites in the regulatory regions of genes involved in bile acid homeostasis.J Mol Biol 2005;346(2):505-519.
37 Xie W,Yeuh MF,Radominska-Pandya A,Saini SP,Negishi Y,Bottroff BS,Cabrera GY,Tukey RH,Evans RM.Control of steroid,heme,and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor.Proc Natl Acad Sci U S A 2003;100(7):4150-4155.
38 Tabb MM,Sun A,Zhou C,Grun F,Errandi J,Romero K,Pham H,Inoue S,Mallick S,Lin M,Forman BM,Blumberg B.Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR.J Biol Chem2003;278(45):43919-43927.
39 Ichikawa T,Horie-Inoue K,Ikeda K,Blumberg B,Inoue S.Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells.J Biol Chem 2006;281(25):16927-16934.
40 Igarashi M,Yogiashi Y,Mihara M,Takada I,Kitagawa H,Kato S.Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene.Mol Cell Biol 2007;27(22):7947-7954.
41 Pascussi JM,Robert A,Nguyen M,Walrant-Debray O,Garabedian M,Martin P,Pineau T,Saric J,Navarro F,Maurel P,Vilarem MJ.Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia.J Clin Invest 2005;115(1):177-186.
42 Zhou C,Assem M,Tay JC,Watkins PB,Blumberg B,Schuetz EG,Thummel KE.Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia.J Clin Invest 2006;116(6):1703-1712.
43 Hosseinpour F,Ellfolk M,Norlin M,Wikvall K.Phenobarbital suppresses vitamin D3 25-hydroxylase expression:a potential new mechanism for drug-induced osteomalacia.Biochem Biophys Res Commun 2007;357(3):603-607.
44 Birringer M,Drogan D,Brigelius-Flohe R.Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation.Free Radic Biol Med 2001;31(2):226-232.
45 Swanson JE,Ben RN,Burton GW,Parker RS.Urinary excretion of 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman is a major route of elimination of gamma-tocopherol in humans.J Lipid Res 1999;40(4):665-671.
46 Landes N,Pfluger P,Kluth D,Birringer M,Ruhl R,Bol GF,Glatt H,Brigelius-Flohe R.Vitamin E activates gene expression via the pregnane X receptor.Biochem Pharmacol 2003;65(2):269-273.
47 Cho JY,Kang DW,Ma X,Ahn SH,Krausz KW,Luecke H,Idle JR,Gonzalez FJ.Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation.J Lipid Res 2009;50(5):924-937.
48 Teng S,Piquette-Miller M.The involvement of the pregnane X receptor in hepatic gene regulation during inflammation in mice.J Pharmacol Exp Ther 2005;312(2):841-848.
49 Beigneux AP,Moser AH,Shigenaga JK,Grunfeld C,Feingold KR.Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR(constitutive androstane receptor)and PXR(pregnane X receptor)in mouse liver during the acute phase response.Biochem Biophys Res Commun 2002;293(1):145-149.
50 Zhou C,Tabb MM,Nelson EL,Grun F,Verma S,Sadatrafiei A,Lin M,Mallick S,Forman BM,Thummel KE,Blumberg B.Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation.J Clin Invest 2006;116(8):2280-2289.
51 Sun M,Cui W,Woody SK,Staudinger JL.Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes.Drug Metab Dispos 2015;43(3):335-343.
2 Orans J,Teotico DG,Redinbo MR.The nuclear xenobiotic receptor pregnane X receptor:recent insights and new challenges.Mol Endocrinol 2005;19(12):2891-2900.
3 Zhang B,Xie W,Krasowski MD.PXR:a xenobiotic receptor of diverse function implicated in pharmacogenetics.Pharmacogenomics 2008;9(11):1695-1709.
4 Umesono K,Evans RM.Determinants of target gene specificity for steroid/thyroid hormone receptors.Cell 1989;57(7):1139-1146.
5 Mangelsdorf DJ,Evans RM.The RXR heterodimers and orphan receptors.Cell 1995;83(6):841-850.
6 Bhalla S,Ozalp C,Fang S,Xiang L,Kemper JK.Ligandactivated 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.
7 Kodama S,Moore R,Yamamoto Y,Negishi M.Human nuclear pregnane X receptor cross-talk with CREB to repress c AMP activation of the glucose-6-phosphatase gene.Biochem J 2007;407(3):373-381.
8 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.
9 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.
10 Zhou J,Zhai Y,Mu Y,Gong H,Uppal H,Toma D,Ren S,Evans RM,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.
11 Gotoh S,Negishi M.Statin-activated nuclear receptor PXRpromotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.Sci Rep 2015;5:14076.
12 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.
13 Rysa J,Buler M,Savolainen MJ,Ruskoaho H,Hakkola J,Hukkanen J.Pregnane X receptor agonists impair postprandial glucose tolerance.Clin Pharmacol Ther 2013;93(6):556-563.
14 Matschinsky FM.GKAs for diabetes therapy:why no clinically useful drug after two decades of trying?Trends Pharmacol Sci 2013;34(2):90-99.
15 Postic C,Shiota M,Niswender KD,Jetton TL,Chen Y,Moates JM,Shelton KD,Lindner J,Cherrington AD,Magnuson MA.Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.J Biol Chem 1999;274(1):305-315.
16 Burcelin R,del Carmen Munoz M,Guillam MT,Thorens B.Liver hyperplasia and paradoxical regulation of glycogen metabolism and glucose-sensitive gene expression in GLUT2-null hepatocytes.Further evidence for the existence of a membrane-based glucose release pathway.J Biol Chem2000;275(15):10930-10936.
17 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.
18 Yoshikawa T,Shimano H,Amemiya-Kudo M,Yahagi N,Hasty AH,Matsuzaka T,Okazaki H,Tamura Y,Iizuka Y,Ohashi K,Osuga J,Harada K,Gotoda T,Kimura S,Ishibashi S,Yamada N.Identification of liver X receptor-retinoid Xreceptor as an activator of the sterol regulatory elementbinding protein 1c gene promoter.Mol Cell Biol 2001;21(9):2991-3000.
19 Misawa K,Horiba T,Arimura N,Hirano Y,Inoue J,Emoto N,Shimano H,Shimizu M,Sato R.Sterol regulatory elementbinding protein-2 interacts with hepatocyte nuclear factor-4to enhance sterol isomerase gene expression in hepatocytes.J Biol Chem 2003;278(38):36176-36182.
20 Kanayama T,Arito M,So K,Hachimura S,Inoue J,Sato R.Interaction between sterol regulatory element-binding proteins and liver receptor homolog-1 reciprocally suppresses their transcriptional activities.J Biol Chem 2007;282(14):10290-10298.
21 Febbraio M,Silverstein RL.CD36:implications in cardiovascular disease.Int J Biochem Cell Biol 2007;39(11):2012-2030.
22 Zhou J,Febbraio M,Wada T,Zhai Y,Kuruba R,He J,Lee JH,Khadem S,Ren S,Li S,Silverstein RL,Xie W.Hepatic fatty acid transporter Cd36 is a common target of LXR,PXR,and PPARgamma in promoting steatosis.Gastroenterology 2008;134(2):556-567.
23 Wolfrum C,Asilmaz E,Luca E,Friedman JM,Stoffel M.Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes.Nature 2004;432(7020):1027-1032.
24 Li T,Chen W,Chiang JY.PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine.J Lipid Res2007;48(2):373-384.
25 Masson D,Lagrost L,Athias A,Gambert P,Brimer-Cline C,Lan L,Schuetz JD,Schuetz EG,Assem M.Expression of the pregnane X receptor in mice antagonizes the cholic acidmediated changes in plasma lipoprotein profile.Arterioscler Thromb Vasc Biol 2005;25(10):2164-2169.
26 Sporstol M,Tapia G,Malerod L,Mousavi SA,Berg T.Pregnane X receptor-agonists down-regulate hepatic ATP-binding cassette transporter A1 and scavenger receptor class B type I.Biochem Biophys Res Commun 2005;331(4):1533-1541.
27 Strott CA.Sulfonation and molecular action.Endocr Rev2002;23(5):703-732.
28 Zhang B,Cheng Q,Ou Z,Lee JH,Xu M,Kochhar U,Ren S,Huang M,Pflug BR,Xie W.Pregnane X receptor as a therapeutic target to inhibit androgen activity.Endocrinology2010;151(12):5721-5729.
29 Zhai Y,Pai HV,Zhou J,Amico JA,Vollmer RR,Xie W.Activation of pregnane X receptor disrupts glucocorticoid and mineralocorticoid homeostasis.Mol Endocrinol 2007;21(1):138-147.
30 Sui Y,Helsley RN,Park SH,Song X,Liu Z,Zhou C.Intestinal pregnane X receptor links xenobiotic exposure and hypercholesterolemia.Mol Endocrinol 2015;29(5):765-776.
31 Fiorucci S,Rizzo G,Donini A,Distrutti E,Santucci L.Targeting farnesoid X receptor for liver and metabolic disorders.Trends Mol Med 2007;13(7):298-309.
32 Xie W,Radominska-Pandya A,Shi Y,Simon CM,Nelson MC,Ong ES,Waxman DJ,Evans RM.An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.Proc Natl Acad Sci U S A 2001;98(6):3375-3380.
33 Sonoda J,Xie W,Rosenfeld JM,Barwick JL,Guzelian PS,Evans RM.Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor(PXR).Proc Natl Acad Sci U S A 2002;99(21):13801-13806.
34 Staudinger JL,Goodwin B,Jones SA,Hawkins-Brown D,MacKenzie KI,LaTour A,Liu Y,Klaassen CD,Brown KK,Reinhard J,Willson TM,Koller BH,Kliewer SA.The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc Natl Acad Sci U S A 2001;98(6):3369-3374.
35 Kast HR,Goodwin B,Tarr PT,Jones SA,Anisfeld AM,Stoltz CM,Tontonoz P,Kliewer S,Willson TM,Edwards PA.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 2002;277(4):2908-2915.
36 Frank C,Makkonen H,Dunlop TW,Matilainen M,Vaisanen S,Carlberg C.Identification of pregnane X receptor binding sites in the regulatory regions of genes involved in bile acid homeostasis.J Mol Biol 2005;346(2):505-519.
37 Xie W,Yeuh MF,Radominska-Pandya A,Saini SP,Negishi Y,Bottroff BS,Cabrera GY,Tukey RH,Evans RM.Control of steroid,heme,and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor.Proc Natl Acad Sci U S A 2003;100(7):4150-4155.
38 Tabb MM,Sun A,Zhou C,Grun F,Errandi J,Romero K,Pham H,Inoue S,Mallick S,Lin M,Forman BM,Blumberg B.Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR.J Biol Chem2003;278(45):43919-43927.
39 Ichikawa T,Horie-Inoue K,Ikeda K,Blumberg B,Inoue S.Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells.J Biol Chem 2006;281(25):16927-16934.
40 Igarashi M,Yogiashi Y,Mihara M,Takada I,Kitagawa H,Kato S.Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene.Mol Cell Biol 2007;27(22):7947-7954.
41 Pascussi JM,Robert A,Nguyen M,Walrant-Debray O,Garabedian M,Martin P,Pineau T,Saric J,Navarro F,Maurel P,Vilarem MJ.Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia.J Clin Invest 2005;115(1):177-186.
42 Zhou C,Assem M,Tay JC,Watkins PB,Blumberg B,Schuetz EG,Thummel KE.Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia.J Clin Invest 2006;116(6):1703-1712.
43 Hosseinpour F,Ellfolk M,Norlin M,Wikvall K.Phenobarbital suppresses vitamin D3 25-hydroxylase expression:a potential new mechanism for drug-induced osteomalacia.Biochem Biophys Res Commun 2007;357(3):603-607.
44 Birringer M,Drogan D,Brigelius-Flohe R.Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation.Free Radic Biol Med 2001;31(2):226-232.
45 Swanson JE,Ben RN,Burton GW,Parker RS.Urinary excretion of 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman is a major route of elimination of gamma-tocopherol in humans.J Lipid Res 1999;40(4):665-671.
46 Landes N,Pfluger P,Kluth D,Birringer M,Ruhl R,Bol GF,Glatt H,Brigelius-Flohe R.Vitamin E activates gene expression via the pregnane X receptor.Biochem Pharmacol 2003;65(2):269-273.
47 Cho JY,Kang DW,Ma X,Ahn SH,Krausz KW,Luecke H,Idle JR,Gonzalez FJ.Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation.J Lipid Res 2009;50(5):924-937.
48 Teng S,Piquette-Miller M.The involvement of the pregnane X receptor in hepatic gene regulation during inflammation in mice.J Pharmacol Exp Ther 2005;312(2):841-848.
49 Beigneux AP,Moser AH,Shigenaga JK,Grunfeld C,Feingold KR.Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR(constitutive androstane receptor)and PXR(pregnane X receptor)in mouse liver during the acute phase response.Biochem Biophys Res Commun 2002;293(1):145-149.
50 Zhou C,Tabb MM,Nelson EL,Grun F,Verma S,Sadatrafiei A,Lin M,Mallick S,Forman BM,Thummel KE,Blumberg B.Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation.J Clin Invest 2006;116(8):2280-2289.
51 Sun M,Cui W,Woody SK,Staudinger JL.Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes.Drug Metab Dispos 2015;43(3):335-343.