BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis

During the last three years there have been a plethora of publications on the liver X-activated receptors (LXRα, NR1H3, and LXRβ, NR1H2), the farnesoid X-activated receptor (FXR, NR1H4), and the pregnane X receptor (PXR, NR1I2) and the role these nuclear receptors play in controlling cholesterol, bile acid, lipoprotein and drug metabolism. The current interest in these nuclear receptors is high, in part, because they appear to be promising therapeutic targets for new drugs that have the potential to control lipid homeostasis. In this review we emphasize i) the role of LXR in controlling many aspects of cholesterol and fatty acid metabolism, ii) the expanded role of FXR in regulating genes that control not only bile acid metabolism but also lipoprotein metabolism, and iii) the regulation of bile acid transport/metabolism in response to bile acid-activated PXR.— Edwards, P. A., H. R. Kast, and A. M. Anisfeld. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J. Lipid Res. 2002. 43: 2–12. During the last three years there have been a plethora of publications on the liver X-activated receptors (LXRα, NR1H3, and LXRβ, NR1H2), the farnesoid X-activated receptor (FXR, NR1H4), and the pregnane X receptor (PXR, NR1I2) and the role these nuclear receptors play in controlling cholesterol, bile acid, lipoprotein and drug metabolism. The current interest in these nuclear receptors is high, in part, because they appear to be promising therapeutic targets for new drugs that have the potential to control lipid homeostasis. In this review we emphasize i) the role of LXR in controlling many aspects of cholesterol and fatty acid metabolism, ii) the expanded role of FXR in regulating genes that control not only bile acid metabolism but also lipoprotein metabolism, and iii) the regulation of bile acid transport/metabolism in response to bile acid-activated PXR. — Edwards, P. A., H. R. Kast, and A. M. Anisfeld. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J. Lipid Res. 2002. 43: 2–12. Nuclear receptors, which include both non-steroidal and steroid receptors, bind to DNA cis elements, known as hormone response elements (HREs) and activate transcription of target genes. Most non-steroidal receptors, such as LXR, FXR, and PXR (liver X-activated receptor, farnesoid X-activated receptor, and pregnane X receptor, respectively), bind DNA as heterodimers with the obligate partner 9-cis retinoic acid receptor α (RXRα, NR2B1) (1Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schütz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. Evans R.M. The nuclear receptor superfamily: the second decade.Cell. 1995; 83: 835-839Google Scholar). HREs are usually composed of direct, inverted, or everted repeats (DR, IR, or ER, respectively) of the idealized sequence AGGTCA that are separated by a variable number (n) of nucleotides (where n = 1–6) to give DRn, IRn, or ERn hormone response elements (2Mangelsdorf D.J. Evans R.M. The RXR heterodimers and orphan receptors.Cell. 1995; 83: 841-850Google Scholar). In general, each nuclear receptor preferentially binds to a limited number of HREs that have a particular spacing and orientation, thus providing specificity for the formation of the protein-DNA complex (2Mangelsdorf D.J. Evans R.M. The RXR heterodimers and orphan receptors.Cell. 1995; 83: 841-850Google Scholar). Functional HREs have been identified in the proximal promoters of target genes, in distal enhancers that can be located ≥22 kb from the transcription start site and in introns (see below). LXR, FXR, PXR, and RXRα, like other members of this large superfamily of transcription factors, have a number of specific functional domains that usually include a poorly understood amino terminal transcriptional activation domain (AF-1), a DNA binding domain (DBD), a ligand binding domain (LBD), domains responsible for nuclear translocation and dimerization, and a transcriptional activation domain (AF-2) at the extreme carboxyl terminus (Fig. 1) (1Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schütz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. Evans R.M. The nuclear receptor superfamily: the second decade.Cell. 1995; 83: 835-839Google Scholar, 3Glass C.K. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers.Endocr. Rev. 1994; 15: 391-407Google Scholar). In general, transcriptional activation is dependent on the entry of a specific ligand, usually a small lipophyllic molecule, into the cavity formed by the LBD of the nuclear receptor. Many, but not all, non-steroidal nuclear receptors are thought to be pre-bound to the HRE in a complex with corepressor proteins. Entry of the ligand into the LBD initiates changes in the conformation of the receptor that results in loss of corepressor proteins, recruitment of coactivator proteins and increased transcription (4Glass C.K. Rosenfeld M.G. The coregulator exchange in transcriptional functions of nuclear receptors.Genes Dev. 2000; 14: 121-141Google Scholar). The role of the corepressor and coactivator proteins in controlling the condensed state of the DNA, via acetylation and deacetylation, has been reviewed recently, but is beyond the scope of the current article (4Glass C.K. Rosenfeld M.G. The coregulator exchange in transcriptional functions of nuclear receptors.Genes Dev. 2000; 14: 121-141Google Scholar, 5Rosenfeld M.G. Glass K.C. Coregulator codes of transcriptional regulation by nuclear receptors.J. Biol. Chem. 2001; 276: 36865-36868Google Scholar). Like many other nuclear receptors, LXR, FXR, and PXR were originally termed orphan nuclear receptors because their natural ligands were unknown at the time that they were initially cloned. With the recent identification of several physiological ligands that activate LXR, FXR, or PXR we can consider that these orphans have been “adopted”. Theseadoptions resulted from a series of elegant studies that identified i) oxysterols [e.g., 24(S),25-epoxycholesterol, 20(S)-, 22(R)-, 24(S)-, and 27-hydroxycholesterol] as activators of LXR (6Forman B.M. Ruan B. Chen J. Schroepfer Jr., G.J. Evans R.M. The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism.Proc. Natl. Acad. Sci. USA. 1997; 94: 10588-10593Google Scholar, 7Lehmann J.M. Kliewer S.A. Moore L.B. Smith-Oliver T.A. Oliver B.B. Su J.L. Sundseth S.S. Winegar D.A. Blanchard D.E. Spencer T.A. Willson T.M. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.J. Biol. Chem. 1997; 272: 3137-3140Google Scholar, 8Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.Nature. 1996; 383: 728-731Google Scholar), ii) primary bile acids, such as chenodeoxycholic acid (CDCA) and cholic acid (CA), as activators of FXR (9Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.M. Moore D.D. Lehmann J.M. Bile acids: natural ligands for an orphan nuclear receptor.Science. 1999; 284: 1365-1368Google Scholar, 10Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Google Scholar, 11Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell. 1999; 3: 543-553Google Scholar), and iii) the secondary bile acid, lithocholic acid (LCA) and its metabolite 3-keto LCA, as activators of PXR (12Staudinger J.L. Goodwin B. Jones S.A. Hawkins-Brown D. MacKenzie K.I. LaTour A. Liu Y. Klassen C.D. Brown K.K. Reinhard J. Willson T.M. Koller B.H. Kliewer S.A. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc. Natl. Acad. Sci. USA. 2001; 98: 3369-3374Google Scholar, 13Xie W. Radominska-Pandya A. Shi Y. Simon C. Nelson M.C. Ong E.S. Waxman D.J. Evans R.M. An essential role for nuclear receptors SXR/RXR in detoxification of cholestatic bile acids.Proc. Natl. Acad. Sci. USA. 2001; 98: 3375-3380Google Scholar) (Fig. 1). The identification of these natural ligands and the generation of mice with deletions in the genes encoding LXRα, LXRβ, FXR, and PXR have opened up new vistas linking the role of these receptors to regulatory functions. A. LXR. LXR was originally isolated from a human liver cDNA library and shown to be most highly expressed in this tissue (14Willy P.J. Umesono K. Ong E.S. Evans R.M. Heyman R.A. Mangelsdorf D.J. LXR, a nuclear receptor that defines a distinct retinoid response pathway.Genes Dev. 1995; 9: 1033-1045Google Scholar). Subsequently, two genes were identified, LXRα and LXRβ (also called RLD-1 and OR-1, respectively), that encode highly conserved isoforms. LXRα is expressed in a tissue specific manner, whereas LXRβ is ubiquitously expressed (15Repa J.J. Mangelsdorf D.J. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis.Annu. Rev. Cell Dev. Biol. 2000; 16: 459-481Google Scholar). Both isoforms bind DNA as a heterodimer with the common partner RXR. LXR/RXR binds preferentially to hormone response elements (LXREs) that consist of two idealized hexanucleotide repeats (AGGTCA) separated by four nucleotides (DR-4) (Fig. 1) (14Willy P.J. Umesono K. Ong E.S. Evans R.M. Heyman R.A. Mangelsdorf D.J. LXR, a nuclear receptor that defines a distinct retinoid response pathway.Genes Dev. 1995; 9: 1033-1045Google Scholar). Subsequently, screens were developed that led to the identification of specific oxysterols as activating ligands for LXR (6Forman B.M. Ruan B. Chen J. Schroepfer Jr., G.J. Evans R.M. The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism.Proc. Natl. Acad. Sci. USA. 1997; 94: 10588-10593Google Scholar, 7Lehmann J.M. Kliewer S.A. Moore L.B. Smith-Oliver T.A. Oliver B.B. Su J.L. Sundseth S.S. Winegar D.A. Blanchard D.E. Spencer T.A. Willson T.M. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.J. Biol. Chem. 1997; 272: 3137-3140Google Scholar, 8Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.Nature. 1996; 383: 728-731Google Scholar). The most potent oxysterols included 24(S),25-epoxycholesterol, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol (7Lehmann J.M. Kliewer S.A. Moore L.B. Smith-Oliver T.A. Oliver B.B. Su J.L. Sundseth S.S. Winegar D.A. Blanchard D.E. Spencer T.A. Willson T.M. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.J. Biol. Chem. 1997; 272: 3137-3140Google Scholar, 8Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.Nature. 1996; 383: 728-731Google Scholar, 16Janowski B.A. Grogan M.J. Jones S.A. Wisely G.B. Kliewer S.A. Corey E.J. Mangelsdorf D.J. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta.Proc. Natl. Acad. Sci. USA. 1999; 96: 266-271Google Scholar). Based on studies with LXR null mice and the identification of a limited number of LXR target genes (Fig. 1), it appears that LXR functions as a sensor of cellular oxysterols. Consistent with this proposal, all LXR target genes encode proteins that have major roles in controlling cholesterol and/or fatty acid homeostasis in a number of tissuesincluding the liver, intestine, macrophages and possibly adipose tissue (Fig. 1, Fig. 2, and Fig. 3). However, the relative importance of LXRα and LXRβ as sterol sensors and their specific roles in regulating gene expression is poorly understood. Recently, synthetic, highly potent LXR ligands were shown to have pronounced effects in vivo. For example, treatment of rodents with such agonists resulted in decreased cholesterol absorption and increased concentrations of plasma triglycerides and phospholipids (17Schultz J.R. Tu H. Luk A. Repa J.J. Medina J.C. Li L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Role of LXRs in control of lipogenesis.Genes Dev. 2000; 14: 2831-2838Google Scholar).Fig. 3.LXR and FXR regulate genes involved in lipid absorption, excretion, and metabolism. The figure illustrates lipid absorption from the intestinal lumen into the villi, the metabolism of lipoproteins in the plasma and the movement of lipids out of macrophages or the liver. Genes that are activated by LXR are shown in green, while FXR target genes are shown in red. The membrane localization of ABCG1A, ABCGX, ABCG5, and ABCG8 are unknown. Other details are provided in the text. The following abbreviations are used: cholesterol (C, yellow droplets; FA, fatty acids; PL, phospholipids; BS, bile salts; IBAT, ileal bile acid transporter; I-BABP, ileal bile acid binding protein; AI, apolipoprotein A-I; E, apolipoprotein E; C-II, apolipoprotein C-II; PLTP, phospholipid transfer protein; LPL, lipoprotein lipase; CM, chylomicrons; CM remnant, chylomicron remnant; LDLR, LDL receptor; ABCG1A, ABCGX, represent different ABCG1 isoforms).View Large Image Figure ViewerDownload (PPT) B. FXR. Rat FXR was originally cloned using PCR and degenerate primers corresponding to the semi-conserved DNA binding domain of nuclear receptors (18Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C.W. Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Google Scholar). At the same time, murine FXR was isolated based on its interaction with RXR and, as a result, was originally referred to as RIP-14 (RXR interacting protein number 14) (19Seol W. Choi H.S. Moore D.D. Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors.Mol. Endocrinol. 1995; 9: 72-85Google Scholar). In the original report, rat FXR was shown to be weakly activated by supraphysiological levels of the isoprenoid farnesol (hence the name FXR) (18Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C.W. Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Google Scholar). Farnesol is derived from the hydrolysis of farnesyl diphosphate in the isoprenoid biosynthetic pathway (Fig. 2) and had previously been shown to function as a signaling molecule in an unrelated pathway that controls the stability of HMG-CoA reductase (20Edwards P.A. Ericsson J. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway.Annu. Rev. Biochem. 1999; 68: 157-185Google Scholar). However, no direct interaction of farnesol with FXR or the LBD of FXR was ever demonstrated. More recent studies have shown that primary bile acids, such as CDCA or CA, bind to FXR in vitro, that this interaction occurs at physiological levels of the bile acids (EC50 of 10–15 μM), that this interaction results in recruitment of coactivators to the liganded FXR, and that there is a subsequent increase in the transcription of target genes (9Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.M. Moore D.D. Lehmann J.M. Bile acids: natural ligands for an orphan nuclear receptor.Science. 1999; 284: 1365-1368Google Scholar, 10Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Google Scholar, 11Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell. 1999; 3: 543-553Google Scholar). All of these properties are consistent with the hypothesis that CDCA and CA function to directly activate FXR in vivo. The hormone response element to which FXR/RXRα binds was originally termed an FXR response element (FXRE) (18Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C.W. Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Google Scholar). This element, however, has also been termed a BARE (bile acid response element), based in part on the more recent studies which indicate that bile acids are the natural ligands for FXR (10Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Google Scholar, 21Grober J. Zaghini I. Fujii H. Jones S.A. Kliewer S.A. Willson T.M. Ono T. Besnard P. Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer.J. Biol. Chem. 1999; 274: 29749-29754Google Scholar). Earlier reportsshow that various degenerate forms of IR-1, DR-3, or DR-4 elements were bound by FXR/RXRα in vitro (18Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C.W. Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Google Scholar, 22Laffitte B.A. Kast H.R. Nguyen C.M. Zavacki A.M. Moore D.D. Edwards P.A. Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor.J Biol Chem. 2000; 275: 10638-10647Google Scholar). With one exception, all published FXR target genes contain one or more degenerate IR-1 elements in the proximal promoter or distal enhancers that function as an FXRE/BARE and are required for transcriptional activation (Fig. 1). In recent studies, we identified an ER-8 as a functional FXRE/BARE that is distinct from all previously identified nuclear hormone response elements (22aKast H.R. Goodwin B. Tarr P.T. Jones S.A. Anisfeld A.M. Stoltz C.M. Tontonoz P. Kliewer S. Willson T.M. Edwards P.A. Regulation of multidrug resistance-associated protein 2 (MRP2; ABCC2) by the nuclear receptors PXR, FXR, and CAR.J. Biol. Chem. 2001; (In press)Google Scholar). Such an observation indicates that the nucleotide sequence of a functional FXRE/BARE may vary considerably. Northern blot assays indicate that FXR transcripts in the rat are restricted to the liver, kidney, intestine (all involved in cholesterol/bile acid metabolism), colon, and adrenals (18Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C.W. Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Google Scholar). As discussed below, the original proposal that FXR might have a role in cholesterol/bile acid homeostasis has proven to be correct (Fig. 2) (18Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C.W. Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Google Scholar). However, the role of FXR in the adrenals is an enigma, since this organ is not known to be involved in any aspect of bile acid metabolism. The finding that androsterone, an intermediate in cholesterol/steroid metabolism, is both synthesized in the adrenals and induces the expression of a reporter gene under the control of an FXRE is certainly intriguing (23Howard W.R. Pospisil J.A. Njolito E. Noonan D.J. Catabolites of cholesterol synthesis pathways and forskolin as activators of the farnesoid X-activated nuclear receptor.Toxicol. Appl. Pharmacol. 2000; 163: 195-202Google Scholar). Demonstration that androsterone, at physiological concentrations, can both bind FXR and activate endogenous FXR-target genes would provide further support for the proposal that this steroid is a natural agonist. C. PXR. The secondary bile acid, lithocholic acid (LCA), is produced from the primary bile acid CDCA by a 7α-dehydroxylation pathway present in certain intestinal bacteria. In contrast to primary bile acids, secondary bile acids are poorly absorbed in the distal ileum. Since LCA has recently been shown to function as a ligand for PXR (see below), we have included a brief section on this nuclear receptor. Far more extensive reviews on PXR are available (23Howard W.R. Pospisil J.A. Njolito E. Noonan D.J. Catabolites of cholesterol synthesis pathways and forskolin as activators of the farnesoid X-activated nuclear receptor.Toxicol. Appl. Pharmacol. 2000; 163: 195-202Google Scholar, 24Kliewer S.A. Willson T.M. Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor.J. Lipid Res. 2002; (In press)Google Scholar, 25Kliewer S.A. Lehmann J.M. Willson T.M. Orphan nuclear receptors: shifting endocrinology into reverse.Science. 1999; 284: 757-760Google Scholar). Murine PXR and its human homolog (hPXR) (also called the steroid and xenobiotic receptor, SXR, or the pregnane activated receptor, PAR) were first cloned in 1998 (26Xie W. Evans R.M. Orphan nuclear receptors: the exotics of xenobiotics.J. Biol. Chem. 2001; 276: 37739-37742Google Scholar, 27Bertilsson G. Heidrich J. Svensson K. Asman M. Jendeberg L. Sydow-Bäckman M. Ohlsson R. Postlind H. Blomquist P. Berkenstam A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction.Proc. Natl. Acad. Sci. USA. 1998; 95: 12208-12213Google Scholar, 28Blumberg B. Sabbagh Jr., W. Juguilon H. Bolado Jr., J. van Meter C.M. Ong E.S. Evans R.M. SXR, a novel steroid and xenobiotic-sensing nuclear receptor.Genes Dev. 1998; 12: 3195-3205Google Scholar, 29Kliewer 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: 73-82Google Scholar). In addition to LCA, a number of naturally occurring steroids, including pregnenolone, progesterone, androstanol, hyperforin (a component of St John's Wort), dexamethasone (a synthetic glucocorticoid), and various xenobiotics (e.g., rifampicin and phenobarbital) have been shown to activate PXR (Fig. 1) (28Blumberg B. Sabbagh Jr., W. Juguilon H. Bolado Jr., J. van Meter C.M. Ong E.S. Evans R.M. SXR, a novel steroid and xenobiotic-sensing nuclear receptor.Genes Dev. 1998; 12: 3195-3205Google Scholar, 29Kliewer 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: 73-82Google Scholar, 30Lehmann J.M. McKee D.D. Watson M.A. Willson T.M. Moore J.T. Kliewer S.A. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.J. Clin. Invest. 1998; 102: 1016-1023Google Scholar, 31Moore L.B. Goodwin B. Jones S.A. Wisely G.B. Serabjit-Singh C.J. Willson T.M. Collins J.L. Kliewer S.A. St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor.Proc. Natl. Acad. Sci. USA. 2000; 97: 7500-7502Google Scholar). The observation that a number of compounds differentially activate murine and human PXR is noteworthy as this may explain the varying responses of mice and humans to certain drugs. The recent observations that the secondary bile acid LCA and its 3-keto metabolite (3-keto LCA) activate PXR are particularly relevant to this review. Accumulation of these natural compounds in the liver is associated with toxicity and cholestasis (12Staudinger J.L. Goodwin B. Jones S.A. Hawkins-Brown D. MacKenzie K.I. LaTour A. Liu Y. Klassen C.D. Brown K.K. Reinhard J. Willson T.M. Koller B.H. Kliewer S.A. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc. Natl. Acad. Sci. USA. 2001; 98: 3369-3374Google Scholar, 13Xie W. Radominska-Pandya A. Shi Y. Simon C. Nelson M.C. Ong E.S. Waxman D.J. Evans R.M. An essential role for nuclear receptors SXR/RXR in detoxification of cholestatic bile acids.Proc. Natl. Acad. Sci. USA. 2001; 98: 3375-3380Google Scholar). As discussed in detail below, the data suggest that PXR functions as a hepatic sensor for many xenobiotics, natural steroids and certain bile acids. Activated PXR then induces the expression of genes that are involved in hepatic uptake, metabolism and subsequent excretion of many of the same compounds (Figs. 1, 2). A. Role of LXR in the intestine. Three genes (ABCA1, ABCG5, and ABCG8) that encode ATP-binding cassette (ABC) transporter proteins have been proposed as LXR target genes in the intestine (32Goodwin B. Hodgson E. Liddle C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module.Mol. 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