International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor

David D. Moore; Shigeaki Kato; Wen Xie; David J. Mangelsdorf; Daniel R. Schmidt; Rui Xiao; Steven A. Kliewer

doi:10.1124/pr.58.4.6

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TABLE 1

Endogenous ligands and primary biologic activities of NR1 subgroup receptors NR1H1 is the insect ecdysone receptor.

Receptor	Major Sites of Expression	Endogenous Ligand/Activator	Primary Function
LXRα (NR1H3)	Liver, intestine, fat, lung, macrophage	Oxysterols	Cholesterol homeostasis
LXRβ (NR1H2)	Broadly expressed	Oxysterols	Cholesterol homeostasis
FXR (NR1H4)	Liver, intestine, kidney	Bile acids	Bile acid homeostasis
VDR (NR1I1)	Intestine, thyroid, kidney	1,25(OH)₂D₃	Calcium homeostasis
CAR (NR1I2)	Liver, intestine, choroid plexus	Bile acids,^a bilirubin^a	Detoxification
PXR (NR1I3)	Liver, intestine	Bile acids	Detoxification

↵ a Elevated levels of bile acids and bilirubin activate CAR indirectly via induction of nuclear translocation, not by functioning directly as agonists

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TABLE 2

CAR

Receptor Nomenclature	NR1I3
Receptor code	4.10.1:XE:1:I3
Other names	MB67
Molecular information	Hs: 348aa, Q14994, chr. 1q23.3¹
	Rn: 358aa, Q9QUS1, chr. 13q24
	Mm: 358aa, Q3V008, chr. 1 H3²
DNA binding
Structure	Heterodimer, RXR partner
HRE core sequence	AGGTCA (DR4, DR5, palindrome)¹^,³^–⁵
Partners
Agonists	TCPOBOP (20 nM),^* meclizine (25 nM), CITCO (49 nM), pregnanedione (670 nM) [EC₅₀]⁴^,⁶^–⁸
Antagonists	Androstanol (400 nM), androstenol (400 nM), meclizine (69 nM), clotrimazole (690 nM) [IC₅₀]⁶^,⁸^,⁹
Coactivator	NCOA1, PPARBP, PGC-1⁹^–¹¹
Corepressor
Biologically important isoforms	CAR1 {Mm}: main isoform in mouse²; CAR2 {Mm}: truncated form, lacking C-terminal sequence²
Tissue distribution	Liver, low levels in the kidney, intestine, stomach {Hs, Mm} [Northern blot, Q-PCR, immunohistology]¹^,²^,¹²^,¹³
Functional assay	Liver hepatomegaly after PB or TCPOBOP treatment {Mm}¹⁴^,¹⁵; drug clearance: recovery from zoxazolamine-induced paralysis {Mm}¹⁵; acetaminophen liver toxicity {Mm}¹⁵
Main target genes	Activated: cytochrome P450 genes {Hs, Mm, Rn},¹⁶ Mdm2 {Mm},¹⁴ MRP2 {Mm}⁵
Mutant phenotype	Impaired drug metabolism induced by specific xenobiotics; resistance to chronic xenobiotic stress-induced liver tumorigenesis {Mm} [knockout]¹⁴^,¹⁵; responsive to human CAR ligands {Mm} [human CAR transgenic with CAR knockout background]¹⁷
Human disease

aa, amino acids; chr., chromosome; HRE, hormonse response element; PPARBP, PPAR-binding protein; Q-PCR, quantitative polymerase chain reaction; PB, phenobarbital
↵* Radioligand
↵1. Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, and Moore DD (1994) A new orphan member of the nuclear hormone receptor superfamily that interacts with subset of retinoic acid response elements. Mol Cell Biol 14: 1544-1552
↵2. Choi HS, Chung M, Tzameli I, Simha D, Lee YK, Seol W, and Moore DD (1997) Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem 272: 23565-23571
↵3. Frank C, Gonzalez MM, Oinonen C, Dunlop TW, and Carlberg C (2003) Characterization of DNA complexes formed by the nuclear receptor constitutive androstane receptor. J Biol Chem 278: 43299-43310
↵4. Tzameli I, Pissios P, Schuetz EG, and Moore DD (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: 2951-2958
↵5. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, and Edwards PA (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: 2908-2915
↵6. Huang W, Zhang J, Wei P, Schrader WT, and Moore DD (2004) Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol Endocrinol 18: 2402-2408
↵7. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, et al. (2003) Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J Biol Chem 278: 17277-17283
↵8. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, et al. (2000) Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275: 15122-15127
↵9. Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM, and Moore DD (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-β Nature 395: 612-615
↵10. Jia Y, Guo GL, Surapureddi S, Sarkar J, Qi C, Guo D, Xia J, Kashireddi P, Yu S, Cho YW, et al. (2005) Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity. Proc Natl Acad Sci USA 102: 12531-12536
↵11. Shiraki T, Sakai N, Kanaya E, and Jingami H (2003) 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 278: 11344-11350
↵12 Nishimura M, Naito S, and Yokoi T (2004)Tissue-specific mRNA expression profiles of human nuclear receptor subfamilies. Drug Metab Pharmacokinet 19: 135-149
↵13. Wei P, Zhang J, Dowhan DH, Han Y, and Moore DD (2002) Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J 2: 117-126
↵14. Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, and Moore DD (2005) Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 19: 1646-1653
↵15. Wei P, Zhang J, Egan-Hafley M, Liang S, and Moore DD (2000) The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature (Lond) 407: 920-923
↵16. Honkakoski P, Sueyoshi T, and Negishi M (2003) Drug-activated nuclear receptors CAR and PXR. Ann Med 35: 172-182
↵17. Zhang J, Huang W, Chua SS, Wei P, and Moore DD (2002) Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298: 422-424, 2002

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TABLE 3

PXR

Receptor Nomenclature	NR1I2
Receptor code	4.10.1:XE:1:I2
Other names	ONR1, BXR, PAR, PRR, PXR, SAR, PAR1, PAR2, PARq
Molecular information	Hs: 434aa, O75469, chr. 3q12-q13.3¹^–³
	Rn: 431aa, Q9R1A7, chr. 11q21⁴
	Mm: 431aa, O54915, chr. 16 B3³
DNA binding
Structure	Heterodimer, RXR partner
HRE core sequence	AGGTCA (DR-3, ER6, DR-4, ER8, IR0, PBRE)³^,⁵^–¹¹
Partners	PIT1 (physical): cellular localization¹²
Agonists	Hyperforin (27 nM), SR12813 (200 nM), pregnenolone-16α-carbonitrile (300 nM), (+)-S20 (0.4 μM), dexamethasone (0.8 μM), schisandrins A and B (1.25–2 μM), rifampicin (0.8–3 μM), 5β -cholestane-3α, 7α, 12α -triol (3–5 μM), taxol (5 μM) [EC₅₀]¹³^–²⁰; lithocholic acid (9–15 μM)^* [IC₅₀]¹¹; vitamin K²¹
Antagonists	Ecteinascidin 743 (3 nM)[IC₅₀]¹⁸
Coactivators	NCOA1, NRIP1, PGC-1, FOXO1, GRIP1³^,²²^–²⁵
Corepressors	SHP, NCOR2¹⁸^,²⁶^,^{2 7}
Biologically important isoforms	PXR1 {Hs}: main isoform¹^,²^,⁵; PXR2 {Hs}: has a different 5′-UTR and encodes a single full-length product with an N-terminal extension not found in other isoforms; PXR3 {Hs}: has a different 5′-UTR and encodes an isoform lacking 39 N-terminal and 37 internal amino acids compared with PXR2—the reading frame is maintained, and it uses a non-AUG translation initiation codon
Tissue distribution	Liver, intestine, kidney, lung {Hs, Mm} [Northern blot, Q-PCR, immunohistology]¹^–⁵^,¹³
Functional assays	Drug clearance by the liver following tribromoethanol-induced anaesthesia or zoxazolamine-induced paralysis {Mm}²⁸; measurement of bile acid liver toxicity after PXR activation {Mm}¹³^,²⁹; bilirubin and corticosterone clearance {Mm}³⁰; warfarin clearance from the liver by PXR-activating Chinese herb wu wei zi (Schisandra chinensis Baill) and gan cao (Glycyrrhiza uralensis Fisch) {Rn}²⁰
Main target genes	Activated: cytochrome P450 genes {Hs, Mm, Rn},¹^–³^,¹⁰^,¹¹^,¹⁸^,²⁸^,³¹ OATP2 {Mm, Rn},³² MRP2 {Hs, Mm},⁷ UGT1A1 {Mm},³⁰ SULT2A {Mm},⁸ MDR1 {Mm},⁶ ALAS-1 {Mm}³³
Mutant phenotype	Impaired drug metabolism induced by specific xenobiotics, such as loss of CYP3A11 inducibility in response to PCN and dexamethasone—sensitivity to bile acid-induced toxicity {Mm} [knockout]¹⁵^,²⁸^,²⁹; acquired responsiveness to human-specific ligands such as rifampicin, loss of responsiveness to rodent-specific ligands, such as PCN {Mm} [hPXR transgenic mice and hPXR transgenic with PXR knockout background]²⁸; increased bilirubin and cortisone clearance, increased detoxification of bile acids, increased protection against xenobiotic toxicants, such as zoxazolamine and tribromoethanol {Mm} [transgenes of a constitutively actived hPXR into the liver]²⁸^–³⁰
Human disease	Breast cancer: levels of PXR mRNA in ER-positive tumors are significantly lower than those observed in ER-negative tumors³⁴; a significant positive correlation was detected between SXR/hPXR labeling index and both the histologic grade and the lymph node status of the carcinomas³⁵

aa, amino acids; chr., chromosome; HRE, hormone response element; PAR, proliferator-activated receptor; UTR, untranslated region; Q-PCR, quantitative polymerase chain reaction; h, human; ER, estrogen receptor; BXR, benzoate X receptor; PBRE, phenobarbital response element
↵* Radioligand
↵1. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P, and Berkenstam A (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA 95: 12208-12213
↵2. Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES and Evans RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12: 3195-3205
↵3. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, et al. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92: 73-82
↵4. Zhang H, LeCulyse E, Liu L, Hu M, Matoney L, Zhu W, and Yan B (1999) Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation. Arch Biochem Biophys 368: 14-22
↵5. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, and Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Investig 102: 1016-1023
↵6. Geick A, Eichelbaum M, and Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276: 14581-14587
↵7. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, and Edwards PA (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: 2908-2915
↵8. Sonoda J, Xie W, Rosenfeld JM, Barwick JL, Guzelian PS, and Evans RM (2002) Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR). Proc Natl Acad Sci USA 99: 13801-13806
↵9. Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, and Evans RM (2000) Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14: 3014-3023
↵10. Goodwin B, Moore L B, Stoltz CM, McKee DD, and Kliewer SA (2001) Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol Pharmacol 60: 427-431
↵11. Ferguson SS, Chen Y, LeCluyse EL, Negishi M, and Goldstein JA (2005) Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4α. Mol Pharmacol 68: 747-757
↵12. Gonzalez MM and Carlberg C (2002) Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors. J Biol Chem 277: 18501-18509
↵13. Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, Tomkinson NC, LeCluyse EL, Lambert MH, Willson TM, et al. (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14: 27-39
↵14. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, and Kliewer SA (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97: 7500-7502
↵15. Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, et al. (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 98: 3369-3374
↵16. Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK, and Forman BM (2003) Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc Natl Acad Sci USA 100: 833-838
↵17. Goodwin B, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, and Repa JJ (2003) Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc Natl Acad Sci USA 100: 223-228
↵18. Synold TW, Dussault I, and Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7: 584-590
↵19. Mu Y, Stephenson CRJ, Kendall C, Saini SPS, Toma D, Cai H, Strom S, Day BW, Wipf P, and Xie W (2005) A PXR agonist with unique species-dependent stereoselectivity and its implications in drug development. Mol Pharmacol 68: 403-413
↵20. Mu Y, Zhang J, Zhang S, Zhou HH, Toma D, Ren S, Huang L, Yaramus M, Baum A, Venkataramanan R, and Xie W (2006) Traditional Chinese medicines wu wei Zi (Schisandra chinensis Baill) and gan cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J Pharmacol Exp Ther 316: 1369-1377
↵21. Tabb MM, Sun A, Zhou C, Grun F, Errandi J, Romero K, Pham H, Inoue S, Mallick S, Lin M, et al. (2003) Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J Biol Chem 278: 43919-43927
↵22. Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, and Parker MG (1995) Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO (Eur Mol Biol Organ) J 14: 3741-3751
↵23. Bhalla S, Ozalp C, Fang S, Xiang L, and Kemper JK (2004) Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1α : functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 279: 45139-45147
↵24. Kodama S, Koike C, Negishi M, and Yamamoto Y (2004) Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol 24: 7931-7940
↵25. Sugatani J, Nishitani S, Yamakawa K, Yoshinari K, Sueyoshi T, Negishi M, and Miwa M (2005) Transcriptional regulation of human UGT1A1 gene expression: activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1. Mol Pharmacol 67: 845-855
↵26. Ourlin JC, Lasserre F, Pineau T, Fabre JM, Sa-Cunha A, Maurel P, Vilarem MJ, and Pascussi JM (2003) The small heterodimer partner interacts with the pregnane X receptor and represses its transcriptional activity. Mol Endocrinol 17: 1693-1703
↵27. Takeshita A, Taguchi M, Koibuchi N, and Ozawa Y (2002) Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem 277: 32453-32458
↵28. Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC, Neuschwander-Tetri BA, Brunt EM, Guzelian PS, and Evans RM (2000) Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature (Lond) 406: 435-439
↵29. Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, Waxman DJ, and Evans RM (2001) An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci USA 98: 3375-3380
↵30. Xie W, Yeuh MF, Radominska-Pandya A, Saini SP, Negishi Y, Bottroff BS, Cabrera GY, Tukey RH, and Evans RM (2003) Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci USA 100: 4150-4155
↵31. Chen Y, Kissling G, Negishi M, and Goldstein JA (2005) The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4α to synergistically activate the human CYP2C9 promoter. J Pharmacol Exp Ther 314: 1125-1133
↵32. Guo GL, Staudinger J, Ogura K, and Klaassen CD (2002) Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16α -carbonitrile is via interaction with pregnane X receptor. Mol Pharmacol 61: 832-839
↵33. Fraser DJ, Zumsteg A, and Meyer UA (2003) Nuclear receptors constitutive androstane receptor and pregnane X receptor activate a drug-responsive enhancer of the murine 5-aminolevulinic acid synthase gene. J Biol Chem 278: 39392-39401
↵34. Dotzlaw H, Leygue E, Watson P and Murphy LC (1999) The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin Cancer Res 5: 2103-2107
↵35. Miki Y, Suzuki T, Kitada K, Yabuki N, Shibuya R, Moriya T, Ishida T, Ohuchi N, Blumberg B, and Sasano H (2006) Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res 66: 535-542

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TABLE 4

FXR

Receptor Nomenclature	NR1H4
Receptor code	4.10.1:BA:1:H4
Other names	BAR, HRR1, RIP14
Molecular information	Hs: 486aa, Q96RI1, chr. 12q23.1
	Rn: 469aa, Q62735, chr. 7q13¹
	Mm: 488aa, Q60641, chr. 10 C2²
DNA binding
Structure	RXR partner
HRE core sequence	AGTTCAnTGAACT
Partners
Agonists	GW4064 (15 nM), fexaramine (250 nM), 22(R)-hydroxycholesterol (>3 μM), lithocholic acid (5 μM), chenodeoxycholic acid (5 μM), cholic acid (>10 μM), deoxycholic acid (100 μM), [EC₅₀]³^–⁸
Antagonists	Guggulsterone (10 μM) [IC₅₀]⁹
Coactivator
Corepressor
Biologically important isoforms	FXRα 1 {Hs, Mm}²^,¹⁰^,¹¹; FXRα 2 {Hs, Mm}²^,¹⁰^,¹¹; FXRα 3 {Hs, Mm}^2,10,11; FXRα 4 {Hs, Mm}²^,¹⁰^,¹¹
Tissue distribution	Liver, small intestine, colon, kidney, adrenal gland {Mm, Rn} [Northern blot, Q-PCR, in situ hybridization]¹^,²^,¹¹
Functional assay
Main target genes	Activated: FGF19 {Hs},¹² FGF15 {Mm},¹³ SHP {Hs, Rn, Mm},¹⁴^,¹⁵ BSEP {Hs, Rn, Mm},¹⁶ IBABP {Hs, Mm},¹⁷ MDR3 {Hs},¹⁸ Mdr2 {Rn, Mm},¹⁹^,²⁰ MRP2 {Hs, Rn},²¹ OATP1B3 {Hs},²² BACS {Hs, Rn},²³ ApoCII {Hs, Mm},²⁴ C3 {Hs},¹³ PDK4 {Hs, Rn, Mm},²⁵ PLTP {Hs, Mm},⁹ PPARα {Hs},²⁶ αA-crystallin {Hs},²⁷ fibrinogen {Hs},²⁸ kininogen {Hs},¹⁸ syndecan-1 {Hs},⁴ VPAC1 {Hs},²⁹ OSTα and OSTβ {Hs}³⁰^–³²; repressed: CYP7A1 {Hs, Rn, Mm},¹⁴^,¹⁵ ABAT {Hs, Mm},³³^,³⁴ NTCP {Rn, Mm},³⁵ APOAI {Hs},³⁶^,³⁷ ApoCIII {Hs, Mm},³⁶ hepatic lipase {Hs},³⁸ SREBP-1c {Mm},³⁹ VLDLR {Hs, Mm}⁴⁰
Mutant phenotype	Elevated serum bile acids, cholesterol and triglycerides; increased hepatic cholesterol and triglycerides; proatherogenic serum lipoprotein profile; reduced bile acid pools and reduced fecal bile acid secretion {Mm} [knockout]⁴¹^,⁴²
Human disease

aa, amino acids; chr., chromosome; HRE, hormone response element; Q-PCR, quantitative polymerase chain reaction; BAR, bile acid receptor; SHP, small heterodimer partner; BSEP, bile salt export pump; IBABP, ileal bile acid-binding protein; BACS, bile acid-CoA synthetase; PLTP, phospholipid transfer protein; OST, organic solute transporter; ABAT, apical bile acid transporter; NTCP, sodium/taurocholate cotransporting polypeptide; APOAI, apolipoprotein A-I; VLDLR, very-low-density lipoprotein receptor
↵1. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, et al. (1995) Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81: 687-693
↵2. Seol W, Choi HS, and Moore DD (1995) Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9: 72-85
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↵7. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, et al. (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science (Wash DC) 284: 1365-1368
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↵10. Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, Haws TF, Kassam A, Powell F, et al. (2002) Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 290: 35-43
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↵14. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, et al. (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6: 517-526
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↵18. Cui J, Huang L, Zhao A, Lew JL, Yu J, Sahoo S, Meinke PT, Royo I, Pelaez F, and Wright SD (2003) Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J Biol Chem 278: 10214-10220
↵19. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, et al. (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217-225
↵20. Jaye MC, Krawiec JA, Campobasso N, Smallwood A, Qiu C, Lu Q, Kerrigan JJ, De Los Frailes Alvaro M, Laffitte B, Liu WS, et al. (2005) Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure. J Med Chem 48: 5419-5422
↵21. Mak PA, Kast-Woelbern HR, Anisfeld AM, and Edwards PA (2002) Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J Lipid Res 43: 2037-2041
↵22. Jung D, Podvinec M, Meyer UA, Mangelsdorf DJ, Fried M, Meier PJ, and Kullak-Ublick GA (2002) Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122: 1954-1966
↵23. Pircher PC, Kitto JL, Petrowski ML, Tangirala RK, Bischoff ED, Schulman IG, and Westin SK (2003) Farnesoid X receptor regulates bile acid-amino acid conjugation. J Biol Chem 278: 27703-27711
↵24. Kast HR, Nguyen CM, Sinal CJ, Jones SA, Laffitte BA, Reue K, Gonzalez FJ, Willson TM, and Edwards PA (2001) Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 15: 1720-1728
↵25. Savkur RS, Thomas JS, Bramlett KS, Gao Y, Michael LF, and Burris TP (2005) Ligand-dependent coactivation of the human bile acid receptor FXR by the peroxisome proliferator-activated receptor γ coactivator-1α. J Pharmacol Exp Ther 312: 170-178
↵26. Pineda Torra I, Freedman LP, and Garabedian MJ (2004) Identification of DRIP205 as a coactivator for the farnesoid X receptor. J Biol Chem 279: 36184-36191
↵27. Lee FY, Kast-Woelbern HR, Chang J, Luo G, Jones SA, Fishbein MC, and Edwards PA (2005) α -Crystallin is a target gene of the farnesoid X-activated receptor in human livers. J Biol Chem 280: 31792-31800
↵28. Anisfeld AM, Kast-Woelbern HR, Lee H, Zhang Y, Lee FY, and Edwards PA (2005) Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling. J Lipid Res 46: 458-468
↵29. Chignard N, Mergey M, Barbu V, Finzi L, Tiret E, Paul A, and Housset C (2005) VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. Hepatology 42: 549-557
↵30. Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL, and Dawson PA (2006) Regulation of the mouse organic solute transporter α -β, Ostα -Ostβ, by bile acids. Am J Physiol 290: G912-G922
↵31. Landrier JF, Eloranta JJ, Vavricka SR, and Kullak-Ublick GA (2006) The nuclear receptor for bile acids, FXR, transactivates the human organic solute transporter-α and -β genes. Am J Physiol 290: G476-G485
↵32. Zollner G, Wagner M, Moustafa T, Fickert P, Silbert D, Gumhold J, Fuchsbichler A, Halilbasic E, Denk H, Marschall HU, et al. (2006) Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter α /β in the adaptive response to bile acids. Am J Physiol 290: G923-G932
↵33. Dussault I, Beard R, Lin M, Hollister K, Chen J, Xiao JH, Chandraratna R, and Forman BM (2003) Identification of gene-selective modulators of the bile acid receptor FXR. J Biol Chem 278: 7027-7033
↵34. Neimark E, Chen F, Li X, and Shneider BL (2004) Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. Hepatology 40: 149-156
↵35. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, and Karpen SJ (2001) The orphan nuclear receptor, SHP, mediates bile acid-induced inhibition of the rat bile acid transporter, NTCP. Gastroenterology 121: 140-147
↵36. Claudel T, Inoue Y, Barbier O, Duran-Sandoval D, Kosykh V, Fruchart J, Fruchart JC, Gonzalez FJ, and Staels B (2003) Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology 125: 544-555
↵37. Srivastava RA, Srivastava N, and Averna M (2000) Dietary cholic acid lowers plasma levels of mouse and human apolipoprotein A-I primarily via a transcriptional mechanism. Eur J Biochem 267: 4272-4280
↵38. Sirvent A, Verhoeven AJ, Jansen H, Kosykh V, Darteil RJ, Hum DW, Fruchart JC, and Staels B (2004) Farnesoid X receptor represses hepatic lipase gene expression. J Lipid Res 45: 2110-2115
↵39. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, and Auwerx J (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Investig 113: 1408-1418
↵40. Sirvent A, Claudel T, Martin G, Brozek J, Kosykh V, Darteil R, Hum DW, Fruchart JC, and Staels B (2004) The farnesoid X receptor induces very low density lipoprotein receptor gene expression. FEBS Lett 566: 173-177
↵41. Kok T, Hulzebos CV, Wolters H, Havinga R, Agellon LB, Stellaard F, Shan B, Schwarz M, and Kuipers F (2003) Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein. J Biol Chem 278: 41930-41937
↵42. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, and Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731-744

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TABLE 5

FXRβ

Receptor Nomenclature	NR1H5
Receptor code	4.10.1:BA:1:H5
Other names
Molecular information	Hs:
	Mm: 505aa, Q80ST6, chr. 3 F2.2¹
DNA binding
Structure	Heterodimer
HRE core sequence	AGTTCA N TGAACT (ER2)
Partners
Agonists	Lanosterol (1 μM), vitamin D₃ (10 μM), cholesten (10 μM), desmosterol (10 μM) [EC₅₀]¹
Antagonists
Coactivator	NCOA1¹
Corepressor
Biologically important isoforms	FXRβ -isoform 1 {Mm}¹; FXRβ -isoform 2 {Mm}: splice variant in exon 8¹; FXRβ -isoform 3 {Mm}: splice variant in exon 10, lacking exon 11¹; FXRβ -isoform 4 {Mm}: splice variants in exon 8 and 10, lacking exon 11¹; FXRβ -isoform 5 {Mm}: splice variant in exon 3¹
Tissue distribution	Ubiquitous {Mm} [RT-PCR]¹
Functional assay
Main target genes
Mutant phenotype
Human disease

aa, amino acids; chr., chromosome; HRE, hormone response element; RT-PCR, reverse transcriptase-polymerase chain reaction
↵1. tte K, Kranz H, Kober I, Thompson P, Hoefer M, Haubold B, Remmel B, Voss H, Kaiser C, Albers M, et al. (2003) Identification of farnesoid X receptor β as a novel mammalian nuclear receptor sensing lanosterol. Mol Cell Biol 23: 864-872

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TABLE 6

LXRα

Receptor Nomenclature	NR1H3
Receptor code	4.10.1:OXY:1:H3
Other names	LXR-a, RLD-1
Molecular information	Hs: 447aa, Q13133, chr. 11p11.2¹
	Rn: 445aa, Q62685, chr. 3q24²
	Mm: 445 aa, Q9Z0Y9, chr. 2 E1³
DNA binding
Structure	RXR partner
HRE core sequence	AGGTCANNNNAGGTCA (DR-4)
Partners	RXR (physical, functional): required for transactivation¹; SHP (physical, functional): represses transactivation⁴; LRH-1 (functional): competence factor⁵
Agonists	Acetyl-podocarpic dimer (1 nM), T0901317 (50 nM), 27-hydroxycholesterol (85 nM), GW3965 (190 nM), 24(S)-hydroxycholesterol (4 μM), 24(S),25-epoxycholesterol (4 μM), paxilline (4 μM), 22(R)-hydroxycholesterol (5 μM) [EC₅₀]⁶^–¹²; F(3)methylAA (13 nM) [K_d]¹³
Antagonists
Coactivator	NCOA1, p300, TRRAP, GRIP1/TIF2, PGC1a, PGC1b¹⁴^–¹⁸
Corepressor	NCOR1, NCOR2¹⁹
Biologically important isoforms
Tissue distribution	Liver, small intestine, kidney, adipose tissue, macrophages, spleen, adrenal gland {Rn} [Northern blot]¹
Functional assay
Main target genes	Activated: ABCA1 {Hs},²⁰^,²¹ ABCG1 {Hs},²²^,²³ SREBP1c {Hs},²⁴ APOCI/IV/II {Hs},²⁵ APOE {Hs},²⁶ APOD {Hs},²⁷ CETP {Hs},⁵ LPL {Hs},²⁸ PLTP {Hs},²⁹^,³⁰ Cyp7A {Mm},¹⁰ FAS {Hs},³¹ GLUT4 {Hs}³²
Mutant phenotype	Inability to tolerate dietary cholesterol; accumulation of hepatic cholesteryl esters resulting in hepatomegaly; increased serum LDL; decreased serum HDL, VLDL, and triglycerides {Mm} [knockout]¹¹^,³³^,³⁴; resistant to obesity when challenged with a diet containing high fat and cholesterol {Mm} [knockout]³⁵
Human disease

aa, amino acids; chr., chromosome; HRE, hormone response element; LDL, low-density lipoprotein; HDL, high-density lipoprotein; VLDL, very-low-density lipoprotein; TRRAP, transformation/transcription domain-associated protein; APOC, apolipoprotein C; APOE, apolipoprotein E; APOD, apolipoprotein D; CETP, cholesteryl ester transfer protein; LPL, lipoprotein lipase; PLTP, phospholipid transfer protein; FAS, fatty acid synthase
↵1. illy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, and Mangelsdorf DJ (1995) LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9: 1033-1045
↵2. pfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, and Pfahl M (1994) A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily. Mol Cell Biol 14: 7025-7035
↵3. lberti S, Steffensen KR, and Gustafsson JA (2000) Structural characterisation of the mouse nuclear oxysterol receptor genes LXRα and LXRβ. Gene 243: 93-103
↵4. rendel C, Schoonjans K, Botrugno OA, Treuter E, and Auwerx J (2002) The small heterodimer partner interacts with the liver X receptor α and represses its transcriptional activity. Mol Endocrinol 16: 2065-2076
↵5. uo Y and Tall AR (2000) Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Investig 105: 513-520
↵6. ramlett KS, Houck KA, Borchert KM, Dowless MS, Kulanthaivel P, Zhang Y, Beyer TP, Schmidt R, Thomas JS, Michael LF, et al. (2003) A natural product ligand of the oxysterol receptor, liver X receptor. J Pharmacol Exp Ther 307: 291-296
↵7. ollins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ, Wilson JG, Tippin TK, Binz JG, et al. (2002) Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 45: 1963-1966
↵8. u X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, and Lund EG (2001) 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276: 38378-38387
↵9. anowski BA, Willy PJ, Devi TR, Falck JR, and Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature (Lond) 383: 728-731
↵10. ehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, and Willson TM (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272: 3137-3140
↵11. chultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, et al. (2000) Role of LXRs in control of lipogenesis. Genes Dev 14: 2831-2838
↵12. parrow CP, Baffic J, Lam MH, Lund EG, Adams AD, Fu X, Hayes N, Jones AB, Macnaul KL, Ondeyka J, et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 MRNA and stimulating cholesterol efflux. J Biol Chem 277: 10021-10027
↵12. enke JG, Macnaul KL, Hayes NS, Baffic J, Chao YS, Elbrecht A, Kelly LJ, Lam MH, Schmidt A, Sahoo S, et al. (2002) A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7α -hydroxylase (CYP7a). Endocrinology 143: 2548-2558
↵14. uuskonen J, Fielding PE, and Fielding CJ (2004) Role of p160 coactivator complex in the activation of liver X receptor. Arterioscler Thromb Vasc Biol 24: 703-708
↵15. in J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, et al. (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell 120: 261-273
↵16. berkofler H, Schraml E, Krempler F, and Patsch W (2003) Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 α. Biochem J 371: 89-96
↵17. ong C, Hiipakka RA, and Liao S (2001) Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. Steroids 66: 473-479
↵18. nno A, Takada I, Takezawa S, Oishi H, Baba A, Shimizu T, Tokita A, Yanagisawa J, and Kato S (2005) TRRAP as a hepatic coactivator of LXR and FXR function. Biochem Biophys Res Commun 327: 933-938
↵19. u X, Li S, Wu J, Xia C, and Lala DS (2003) Liver X receptors interact with corepressors to regulate gene expression. Mol Endocrinol 17: 1019-1026
↵20. ostet P, Luo Y, Wang N, and Tall AR. (2000) Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275: 28240-28245
↵21. epa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, and Mangelsdorf DJ (2000) Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524-1529
↵22. ennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, and Edwards PA (2001) Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem 276: 39438-39447
↵23. enkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, and Edwards PA (2000) Human white/murine ABC8 MRNA levels are highly induced in lipid-loaded macrophages: a transcriptional role for specific oxysterols. J Biol Chem 275: 14700-14707
↵24. epa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, and Mangelsdorf DJ (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev 14: 2819-2830
↵25. ak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK, Mangelsdorf DJ, Tontonoz P and Edwards PA (2002) Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages: a critical role for nuclear liver X receptors α and β. J Biol Chem 277: 31900-31908
↵26. affitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, and Tontonoz P (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98: 507-512
↵27. ummasti S, Laffitte BA, Watson MA, Galardi C, Chao LC, Ramamurthy L, Moore JT, and Tontonoz P (2004) Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of ApoD as a direct target. J Lipid Res 45: 616-625
↵28. hang Y, Repa JJ, Gauthier K, and Mangelsdorf DJ (2001) Regulation of lipoprotein lipase by the oxysterol receptors, LXRα and LXRβ. J Biol Chem 276: 43018-43024
↵29. ao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H, Ryan TP, Liang Y, et al. (2002) Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem 277: 39561-39565
↵30. affitte BA, Joseph SB, Chen M, Castrillo A, Repa J, Wilpitz D, Mangelsdorf D, and Tontonoz P (2003) The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Mol Cell Biol 23: 2182-2191
↵31. oseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, and Tontonoz P (2002) Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277: 11019-11025
↵32. alen KT, Ulven SM, Bamberg K, Gustafsson JA, and Nebb HI (2003) Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor α. J Biol Chem 278: 48283-48291
↵33. eet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, and Mangelsdorf DJ (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR α. Cell 93: 693-704
↵34. chuster GU, Parini P, Wang L, Alberti S, Steffensen KR, Hansson GK, Angelin B, and Gustafsson JA (2002) Accumulation of foam cells in liver X receptor-deficient mice. Circulation 106: 1147-1153
↵35. alaany NY, Gauthier KC, Zavacki AM, Mammen PP, Kitazume T, Peterson JA, Horton JD, Garry DJ, Bianco AC, and Mangelsdorf DJ (2005) LXRs regulate the balance between fat storage and oxidation. Cell Metab 1: 231-244

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TABLE 7

LXRβ

Receptor Nomenclature	NR1H2
Receptor code	4.1.1:OXY:1:H2
Other names	LXR-b, UNR, OR-1, NER, NER1, RIP15
Molecular information	Hs: 461aa, P55055, chr. 19q13.3¹
	Rn: 446aa, Q62755, chr. 1q22²
	Mm: 446aa, Q60644, chr. 7 B3³
DNA binding
Structure	RXR partner
HRE core sequence	AGGTCANNNNAGGTCA (DR-1, DR-4)
Partners	RXR (physical)³; SHP (physical, functional)⁴
Agonists	Acetyl-podocarpic dimmer (1 nM), GW3965 (30 nM), T0901317 (50 nM), 27-hydroxycholesterol (71 nM), 22(R)-hydroxycholesterol (3 μM), 24(S)-hydroxycholesterol (3 μM), 24(S),25-epoxycholesterol (3 μM),^* paxilline (4 μM), [EC₅₀]⁵^–¹¹; F(3)methylAA (7 nM) [K_d]¹²
Antagonists
Coactivator	NCOA1, p300¹³
Corepressor	NCOR1, NCOR2¹⁴
Biologically important isoforms
Tissue distribution	Ubiquitous {Rn} [Northern blot]²^,¹⁵
Functional assay
Main target genes	Activated: ABCA1 {Hs},¹⁶^,¹⁷ ABCG1 {Hs},¹⁸^,¹⁹ SREBP1c {Hs},²⁰ APOCI/IV/II {Hs},²¹ APOE {Hs},²² CETP {Hs},²³ Cyp7A {Mm},⁹ FAS {Hs},²⁴ GLUT4 {Hs}²⁵
Mutant phenotype	Alterations in adipocyte growth, glucose homeostasis, and β -cell function (normal resistance to dietary cholesterol, unlike the LXRα knockout) {Mm} [knockout]²⁶^,²⁷
Human disease

aa, amino acids; chr., chromosome; HRE, hormone response element; UNR, ubiquitously expressed nuclear receptor; APOC, apolipoprotein C; APOE, apolipoprotein E; CETP, cholesteryl ester transfer protein; FAS, fatty acid synthase
↵* Radioligand
↵1. Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, and Schmidt A (1994) NER, a new member of the gene family encoding the human steroid hormone nuclear receptor. Gene 147: 273-276
↵2. Song C, Kokontis JM, Hiipakka RA, and Liao S (1994) Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc Natl Acad Sci USA 91: 10809-10813
↵3. Seol W, Choi HS, and Moore DD (1995) Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9: 72-85
↵4. Brendel C, Schoonjans K, Botrugno OA, Treuter E, and Auwerx J (2002) The small heterodimer partner interacts with the liver X receptor α and represses its transcriptional activity. Mol Endocrinol 16: 2065-2076
↵5. Bramlett KS, Houck KA, Borchert KM, Dowless MS, Kulanthaivel P, Zhang Y, Beyer TP, Schmidt R, Thomas JS, Michael LF, et al. (2003) A natural product ligand of the oxysterol receptor, liver X receptor. J Pharmacol Exp Ther 307: 291-296
↵6. Collins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ, Wilson JG, Tippin TK, Binz JG, et al. (2002) Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 45: 1963-1966
↵7. Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, and Lund EG (2001) 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276: 38378-38387
↵8. Janowski BA, Willy PJ, Devi TR, Falck JR, and Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR α. Nature (Lond) 383: 728-371
↵9. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, et al. (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272: 3137-3140
↵10. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, et al. (2000) Role of LXRs in control of lipogenesis. Genes Dev 14: 2831-2838
↵11. Sparrow CP, Baffic J, Lam MH, Lund EG, Adams AD, Fu X, Hayes N, Jones AB, Macnaul KL, Ondeyka J, et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 MRNA and stimulating cholesterol efflux. J Biol Chem 277: 10021-10027
↵12. Menke JG, Macnaul KL, Hayes NS, Baffic J, Chao YS, Elbrecht A, Kelly LJ, Lam MH, Schmidt A, Sahoo S, et al. (2002) A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7α -hydroxylase (CYP7a). Endocrinology 143: 2548-2558
↵13. Huuskonen J, Fielding PE, and Fielding CJ (2004) Role of p160 coactivator complex in the activation of liver X receptor. Arterioscler Thromb Vasc Biol 24: 703-708
↵14. Hu X, Li S, Wu J, Xia C, and Lala DS (2003) Liver X receptors interact with corepressors to regulate gene expression. Mol Endocrinol 17: 1019-1026
↵15. Lu TT, Repa JJ, and Mangelsdorf DJ (2001) Orphan nuclear receptors as elixirs and fixers of sterol metabolism. J Biol Chem 276: 37735-37738
↵16. Costet P, Luo Y, Wang N, and Tall A (2000) Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275: 28240-28245
↵17. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, and Mangelsdorf DJ (2000) Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science (Wash DC) 289: 1524-1529
↵18. Kennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, and Edwards PA (2001) Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem 276: 39438-39447
↵19. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, and Edwards PA (2000) Human white/murine ABC8 MRNA levels are highly induced in lipid-loaded macrophages: a transcriptional role for specific oxysterols. J Biol Chem 275: 14700-14707
↵20. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, and Mangelsdorf DJ (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev 14: 2819-2830
↵21. Mak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK, Mangelsdorf DJ, Tontonoz P, and Edwards PA (2002) Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages: a critical role for nuclear liver X receptors α and β. J Biol Chem 277: 31900-31908
↵22. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, and Tontonoz P (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98: 507-512
↵23. Luo Y and Tall AR (2000) Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Investig 105: 513-520
↵24. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, and Tontonoz P (2002) Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277: 11019-11025
↵25. Dalen KT, Ulven SM, Bamberg K, Gustafsson JA, and Nebb HI (2003) Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor α. J Biol Chem 278: 48283-48291
↵26. Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Bjorkhem I, Pettersson S, and Gustafsson JA (2001) Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ -deficient mice. J Clin Investig 107: 565-573
↵27. Gerin I, Dolinsky VW, Shackman JG, Kennedy RT, Chiang SH, Burant CF, Steffensen KR, Gustafsson JA, and MacDougald OA (2005) LXRβ is required for adipocyte growth, glucose homeostasis, and β cell function. J Biol Chem 280: 23024-23031

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TABLE 8

VDR

Receptor Nomenclature	NR1I1
Receptor code
Other names
Molecular information	Hs: 427aa, P11473, chr. 12q13.11¹
	Rn: 423aa, P13053, chr. 7q36²
	Mm: 422aa, P48281, chr. 15 F1³
DNA binding
Structure	Heterodimer, RXR partner
HRE core sequence	DR-3
Partners
Agonists	KH1060 (6.5 × 10^–11 M), EB1089 (2.7 × 10^–10 M), 1α ,25-(OH)₂D₃ (6.2 × 10^–10 M),^* 25-OHD₃ (1.2 × 10^–9 M), (23S,25R)-1α ,25-(OH)₂D₃-26,23-lactone (3.1 × 10^–8 M) [K_d]⁴^–⁷; 2MD (1 × 10^–10 M) [ED₅₀]⁸; MC903 (131), TV-02 (66), F₆-1α ,25(OH)₂D₃ (45), Gemini [1R,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D₃] (38), OCT (10) [RCI]⁵^,⁹^–¹³; Ro-26-9228 (6.2 × 10^–9 M) [IC₅₀]¹⁴; LG190178 (1.5 × 10^–7 M), 3-keto-LCA (2.9 × 10^–7 M), LCA (8 × 10^–6 M) [K_i]¹⁵^,¹⁶; ED-71, 1α -OHD₂, 19-nor-1α ,25(OH)₂D₂¹⁷^,¹⁸
Antagonists	TEI-9647 (10), ZK159222 (7) [RCI]¹⁹^,²⁰
Coactivator
Corepressor
Biologically important isoforms
Tissue distribution
Functional assay
Main target genes
Mutant phenotype	Knockout mice exhibit typical rachitic features such as hypocalcemia, hyperparathyroidism, impaired bone formation, uterine hypoplasia, growth retardation, and alopecia after weaning; they also have an impaired insulin secretory capacity {Mm} [knockout²¹^–²³]
Human disease	Vitamin D-dependent rickets type II²⁴^,²⁵

aa, amino acids; chr., chromosome; HRE, hormone response element; OCT, 22-oxa-1α ,25-dihydroxyvitamin-D₃; LCA, lithocholic acid; RCI, relative competitive index
↵* Radioligand
↵1. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J, and O'Malley BW (1988) Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 85: 3294-3298
↵2. Burmester JK, Maeda N, and DeLuca HF (1988) Isolation and expression of rat 1,25-dihydroxyvitamin D₃ receptor cDNA. Proc Natl Acad Sci USA 85: 1005-1009
↵3. Kamei Y, Kawada T, Fukuwatari T, Ono T, Kato S, and Sugimoto E (1995) Cloning and sequencing of the gene encoding the mouse vitamin D receptor. Gene 152: 281-282
↵4. Wiberg K, Ljunghall S, Binderup L, and Ljunggren O (1995) Studies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitro. Bone 17: 391-395
↵5. Bishop JE, Collins ED, Okamura WH, and Norman AW (1994) Profile of ligand specificity of the vitamin D binding protein for 1α ,25-dihydroxyvitamin D₃, and its analogs. J Bone Miner Res 9: 1277-1288
↵6. Erben RG, Soegiarto DW, Weber K, Zeitz U, Lieberherr M, Gniadecki R, Möller G, Adamski J, and Balling R (2002) Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D. Mol Endocrinol 16: 1524-1537
↵7. Shiina Y, Abe E, Miyaura C, Tanaka H, Yamada S, Ohmori M, Nakayama K, Takayama H, Matsunaga I, Nishii Y, et al. (1983) Biological activity of 24,24-difluoro-1α ,25-dihydroxyvitamin D₃ and 1α ,25-dihydroxyvitamin D₃-26,23-lactone in inducing differentiation of human myeloid leukemia cells. Arch Biochem Biophys 220: 90-94
↵8. Sicinski RR, Prahl JM, Smith CM, and DeLuca HF (1998) New 1α ,25-dihydroxy-19-norvitamin D₃ compounds of high biological activity: synthesis and biological evaluation of 2-hydroxymethyl, 2-methyl, and 2-methylene analogues. J Med Chem 41: 4662-4674
↵9. Ikeda M, Takahashi K, Dan A, Koyama K, Kubota K, Tanaka T, and Hayashi M Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D₃. Bioorg Med Chem 8: 2157-2166
↵10. Weyts FA, Dhawan P, Zhang X, Bishop JE, Uskokovic MR, Ji Y, Studzinski GP, Norman AW, and Christakos S (2004) Novel Gemini analogs of 1α ,25-dihydroxyvitamin D₃ with enhanced transcriptional activity. Biochem Pharmacol 67: 1327-1336
↵11. Abe J, Takita Y, Nakano T, Miyaura C, Suda T, and Nishii Y (1989) A synthetic analogue of vitamin D, 22-oxa-1α ,25-dihydroxyvitamin D₃, is a potent modulator of in vivo immunoregulating activity without inducing hypercalcemia in mice. Endocrinology 124: 2645-2647
↵12. Sato K, Nishii Y, Woodiel FN, and Raisz LG (1993) Effects of two new vitamin D₃ derivatives, 22-oxa-1α ,25-dihydroxyvitamin-D₃ (OCT) and 2β-(3-hydroxypropoxy)-1α ,25-dihydroxyvitamin-D₃ (ED-71), on bone metabolism in organ culture. Bone 14: 47-51
↵13. Okano T, Tsugawa N, Masuda S, Takeuchi A, Kobayashi T, and Nishii Y (1989) Protein-binding properties of 22-oxa-1α ,25-dihydroxyvitamin D, a synthetic analogue of 1α ,25-dihydroxyvitamin D. J Nutr Sci Vitaminol (Tokyo) 35: 529-533
↵14. Peleg S, Uskokovic M, Ahene A, Vickery B, and Avnur Z (2002) Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog Ro-26-9228 in osteopenic rats. Endocrinology 143: 1625-1636
↵15. Boehm MF, Fitzgerald P, Zou A, Elgort MG, Bischoff ED, Mere L, Mais DE, Bissonnette RP, Heyman RA, Nadzan AM, et al. (2002) Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D₃. Chem Biol 6: 265-275
↵16. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, and Mangelsdorf DJ (2002) Vitamin D receptor as an intestinal bile acid sensor. Science (Wash DC) 296: 1313-1316
↵17. Miyamoto K, Murayama E, Ochi K, Watanabe H, and Kubodera N (1993) Synthetic studies of vitamin D analogues. XIV. Synthesis and calcium regulating activity of vitamin D₃ analogues bearing a hydroxyalkoxy group at the 2β -position. Chem Pharm Bull (Tokyo) 41: 1111-1113
↵18. Okano T, Tsugawa N, Masuda S, Takeuchi A, Kobayashi T, Takita Y, and Nishii Y (1989) Regulatory activities of 2 β -(3-hydroxypropoxy)-1α ,25-dihydroxyvitamin D₃, a novel synthetic vitamin D₃ derivative, on calcium metabolism. Biochem Biophys Res Commun 163: 1444-1449
↵19. Miura D, Manabe K, Ozono K, Saito M, Gao Q, Norman AW, and Ishizuka S (1999) Antagonistic action of novel 1α ,25-dihydroxyvitamin D₃-26, 23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1α ,25-dihydroxyvitamin D3. J Biol Chem 274: 16392-16399
↵20. Fujishima T, Kojima Y, Azumaya I, Kittaka A, and Takayama H (2003) Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications: remarkable effects of 2α -methyl introduction on antagonistic activity. Bioorg Med Chem 11: 3621-3631
↵21. Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T, Arioka K, Sato H, Uchiyama Y, et al. (1997) Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16: 391-396
↵22. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, and Demay MB (1997) Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA 94: 9831-9835
↵23. Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, and Erben RG (2003) Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J 17: 509-511
↵24. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, and O'Malley BW (1988) Point mutations in the human vitamin D receptor associated with hypocalcemic rickets. Science (Wash DC) 242: 1702-1705
↵25. Malloy PJ, Pike JW, and Feldman D (1999) The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 20: 156-188