EBM Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

First published online June 5, 2008
Experimental Biology and Medicine 233:1191-1201 (2008)
doi: 10.3181/0802-MR-50
© 2008 by the Society for Experimental Biology and Medicine
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
233/10/1191    most recent
0802-MR-50v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wada, T.
Right arrow Articles by Xie, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wada, T.
Right arrow Articles by Xie, W.

MINIREVIEW

The Emerging Role of Nuclear Receptor ROR{alpha} and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation

Taira Wada*, Hong Soon Kang{dagger}, Anton M. Jetten{dagger} and Wen Xie*,1

* Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and {dagger} Cell Biology Section, Division of Intramural Research, The National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

1 To whom requests for reprints should be addressed at Center for Pharmacogenetics, University of Pittsburgh, 3501 Terrace St., 633 Salk Hall, Pittsburgh, PA 15261. E-mail: wex6{at}pitt.edu


   Abstract
Top
 Abstract
Introduction
 References
 
Retinoid-related orphan receptors (RORs), including the {alpha}, β and {gamma} isoforms (NR1F1–3), are orphan nuclear receptors that have been implicated in tissue development, immune responses, and circadian rhythm. Although ROR{alpha} and ROR{gamma} have been shown to be expressed in the liver, the hepatic function of these two RORs remains unknown. We have recently shown that loss of ROR{alpha} and/or ROR{gamma} can positively or negatively influence the expression of multiple Phase I and Phase II drug metabolizing enzymes and transporters in the liver. Among ROR responsive genes, we identified oxysterol 7{alpha}-hydroxylase (Cyp7b1), which plays a critical role in the homeostasis of cholesterol, as a ROR{alpha} target gene. We showed that ROR{alpha} is both necessary and sufficient for Cyp7b1 activation. Studies of mice deficient of ROR{alpha} or liver X receptors (LXRs) revealed an interesting and potentially important functional crosstalk between ROR{alpha} and LXR. The respective activation of LXR target genes and ROR target genes in ROR{alpha} null mice and LXR null mice led to our hypothesis that these two receptors are mutually suppressive in vivo. LXRs have been shown to regulate a battery of metabolic genes. We conclude that RORs participate in the xeno- and endobiotic regulatory network by regulating gene expression directly or through crosstalk with LXR, which may have broad implications in metabolic homeostasis.

Key Words: nuclear receptor • gene regulation • metabolism


   Introduction
Top
 Abstract
 Introduction
References
 
Nuclear steroid hormone receptors were first cloned in the middle 1980s, and they have since been established as ligand-dependent transcriptional factors. This subsequently led to the identification of many so-called "orphan nuclear receptors" based on their homology to the traditional steroid hormone receptors (1). Genomic studies have indicated that there are 48 and 50 nuclear receptor genes in rodents and humans, respectively. Most, if not all, nuclear receptors contain a N-terminal DNA binding domain (DBD) and a C-terminal ligand binding domain (LBD) (Fig. 1AGo). Nuclear receptors often regulate gene expression by binding, as homodimers, retinoid X receptor (RXR) heterodimers or as monomers, to their responsive elements present in target gene promoters (Fig. 1BGo).


Figure 1
View larger version (21K):
[in this window]
[in a new window]

  		Figure 1. General signaling of nuclear receptors. (A) General domain structure of a nuclear receptor. (B) Nuclear receptors can regulate gene expression by binding to the hormone response element (HRE) as homodimers, RXR heterodimers, or monomers. ROR and LXR are used as examples. RORE, ROR response element.

 
The nuclear receptor superfamily has been shown to be involved in numerous biological processes, ranging from development to reproduction, metabolism, cell proliferation, differentiation and apoptosis (2). Due to their physiological significance, many of the nuclear receptors have been explored as therapeutic targets for various diseases, a development that has been facilitated by major advances in the identification and characterization of receptor agonists and antagonists. Although the ligands of some nuclear receptors remain unknown and some receptors might be true "orphan receptors", the function of these orphan receptors can still be revealed by the creation and characterization of gene knockout mice. This review will focus on the novel function of the orphan receptor ROR{alpha} in xeno- and endobiotic gene regulation.

Orphan Nuclear Receptor ROR{alpha}
Retinoid-related orphan receptors (RORs) are members of the nuclear receptors that include three isoforms: ROR{alpha} (NR1F1), RORβ (NR1F2) and ROR{gamma} (NR1F3) (3). Each ROR isoform has a distinct pattern of tissue distribution (4). ROR{alpha} is expressed in many tissues, including cerebellar Purkinje cells, liver, thymus, skeletal muscle, skin, lung and kidney (5, 6). RORβ exhibits a more restricted pattern of expression and is expressed in several regions of the central nervous system, retina, and pineal gland. ROR{gamma} is most highly expressed in thymus but also detectable in many other tissues, including liver, kidney and muscle (3, 7, 8). The functional ligands of RORs remain elusive. It was reported that cholesterol and its sulfonated derivatives might function as ROR{alpha} ligands (9). Other ligands suggested to bind to ROR{alpha} are melatonin (10) and thiazolidinediones (11). To our knowledge, none of these have been established as functional ligands for ROR{alpha}. Evidence has been provided indicating that certain retinoids, including all-trans retinoic acid, can function as partial antagonists for RORβ and ROR{gamma} (12).

RORs bind either as monomers to the ROR-response elements (RORE) within the target gene promoter regions. ROREs are composed of 6-bp A/T-rich region immediately preceding a consensus AGGTCA motif (8, 13). However, ROR{alpha} has been demonstrated to be able to bind as a homodimer to direct repeats of the consensus AGGTCA motif separated by two base pairs (DR2) (14). Like many other nuclear receptors, RORs are composed of a N-terminal DBD and a LBD located at the C-terminal. ROR isoforms share a highly conserved DBD but they are more diverse in their LBDs (Fig. 2Go). The transcriptional activities of RORs are negatively and positively regulated through the recruitment of nuclear receptor co-repressors and co-activators, respectively. It has been reported that co-repressors (N-CoR, RIP140 and SMRT) and co-activator (GRIP, PBP, SRC1, CBP and PGC1{alpha}) can interact with ROR{alpha} (14–18). It was proposed that cell-specific interactions with specific co-regulators may contribute to the molecular mechanism for distinct physiological functions of ROR{alpha} (14).


Figure 2
View larger version (8K):
[in this window]
[in a new window]

  		Figure 2. Comparison of the homology among three ROR isoforms. Percentages indicate amino acid identities in the DNA-binding domain (DBD) and ligand-binding domain (LBD) compared to ROR{alpha}. The positions of amino acids are also labeled.

 
Characterizations of ROR null mice have revealed a number of important physiological functions of RORs. ROR{alpha}–/– mice show an ataxic phenotype similar to that observed in the Staggerer (sg/sg) mutant mice, which carry a natural deletion in the LBD, causing a frame shift and a truncated ROR{alpha} protein (5, 6). The ROR{alpha}sg/sg mice exhibit a variety of phenotypes, including, cerebellar degeneration, abnormal circadian behavior, vascular dysfunction, muscular irregularities, osteoporosis, atherosclerosis and altered immune responses, as summarized in Table 1Go (19–25). The atherosclerotic phenotype in the ROR{alpha}sg/sg mice was associated with a marked hypo-{alpha}-lipoproteinemia due to a decreased expression of ApoAI, a transcriptional target of ROR{alpha} in the intestine (26). In the vascular system, ROR{alpha} is involved in postischemic angiogenesis and differentiation and contractile function of smooth muscle cells (27). The ROR{alpha}sg/sg mice exhibit more extensive angiogenesis, leading to an increase of inflammatory cytokine production and eNOS protein level (28), suggesting ROR{alpha} as a potent negative regulator of ischemia-induced angiogenesis. Inflammation is associated with both atherosclerosis and angiogenesis. The ROR{alpha}sg/sg mice also have a delayed lymphocyte development, which may partially be accounted for by ROR{alpha}-mediated transcriptional activation of I{kappa}B{alpha}, the inhibitor of NF-kB (29) and ROR{alpha}sg/sg mice are less sensitive to autoimmune and allergy-induced inflammation (20, 35). We recognize that the effect of ROR{alpha} on inflammation is a complex issue. ROR{alpha} has been shown to enhance IkB{alpha} expression thereby inhibiting NF-kB (in vitro studies), whereas in vivo ROR{alpha}sg/sg mice are less sensitive to autoimmune and allergy-induced inflammation. This may in part be in part related to changes in thymocyte populations.


View this table:
[in this window]
[in a new window]

  		Table 1. Summary of Known Functions of ROR{alpha}
 
Among other ROR isoforms, RORβ is believed to be involved in the processing of sensory information, as RORβ–/– mice showed significant phenotypes in circadian behaviors and retinal degeneration (30). RORβ has been reported to regulate the blue opsin gene in cone photoreceptor development (31). ROR{gamma}–/– mice lacked all lymph nodes and Peyer’s patches, and contained reduced number of thymocytes (17, 32, 33) suggesting that ROR{gamma} plays an essential role in lymphoid organogenesis and thymopoiesis. Recent studies have demonstrated an important role for both ROR{alpha} and ROR{gamma} in the differentiation of naïve T cells into Th17 cells (34, 35).

Nuclear Receptors and Xeno- and Endobiotic Metabolism
The metabolic homeostasis of foreign chemicals (xenobiotics, including drugs) and endogenous compounds (endobiotics) is essential for the survival of mammals. Xenobiotic metabolism is facilitated by the Phase I and Phase II drug metabolizing enzymes, as well as drug transporters (36, 37). The Phase I reactions include oxidation, reduction, hydrolysis and hydration. The cytochrome P450 (CYP) enzymes play a critical and dominating role in Phase I reactions. Phase II metabolism includes sulfation (mediated by sulfotransferases or SULTs), glucuronidation (mediated by UDP-glucoronosyltransferases or UGTs), or glutathione conjugation (mediated by glutathione S-transferases or GSTs). Products generated by Phase I metabolism are generally more polar and can be better substrates for Phase II conjugations. The conjugation by Phase II enzymes results in increased polarity and solubility of xenobiotics and promotes xenobiotic excretion. Drug transporters, which are not the focus of this review, are responsible for the uptake and efflux of parent or biotransformed xenobiotics.

Although the structure and function of Phase I and Phase II enzymes have been subjects of extensive studies for several decades and it has been known that the expression of many drug metabolizing enzymes is inducible, little is known about the transcriptional regulators that control the production of these enzymes. In the late 90s, the role of nuclear receptors in the transcriptional regulation of drug metabolizing enzymes began to emerge, which was highlighted by the cloning of the xenobiotic receptor pregnane X receptor (PXR) (38–41) and characterization of the constitutive androstane receptor (CAR) as another important xenobiotic nuclear receptor (42, 43). In the past 10 years, considerable advances have been made in establishing nuclear receptors as master regulators of the expression of Phase I and Phase II drug metabolizing enzymes and transporters (Fig. 3Go) (36, 37).


Figure 3
View larger version (26K):
[in this window]
[in a new window]

  		Figure 3. Proposed model of nuclear receptor-mediated regulation of drug metabolizing enzymes and transporters. Activation of nuclear receptor may result in the concerted regulation of Phase I and Phase II enzymes and the "Phase III" drug transporters. ROR and LXR are used as examples.

 
In addition to PXR and CAR, several other nuclear receptors, such as vitamin D receptor (VDR), hepatic nuclear factor 4{alpha} (HNF4{alpha}), peroxisome proliferator-activated receptors (PPARs) and farnesoid X receptor (FXR), have also been implicated in the regulation of xenobiotic enzymes and transporters (44–47). More recently, results from our lab have shown that the liver X receptor (LXR), a previously known sterol sensor, can also regulate the expression of Phase II sulfotransferases, such as the bile acid detoxifying hydroxysteroid sulfotransferase Sult2a9/2a1 (48) and the estrogen sulfotransferase (Est/Sult1e1) (49).

It is conceivable that nuclear receptor-mediated regulation of drug metabolizing enzymes has implications in drug metabolism, drug toxicity and drug-drug interactions. Interestingly, the same metabolic enzyme and transporter systems are responsible for the metabolism of numerous endobiotics, such as steroid hormones, bile acids and lipid metabolites (50). Consistent with this notion, studies have implicated nuclear receptor-mediated enzyme and transporter regulation in many pathophysiological conditions by impacting the homeostasis of endobiotics. Examples include the role of PXR and CAR in hyperbilirubinemia (51–53) and cholestasis (41, 54–57), and the role of LXR in cholestasis (48) and estrogen homeostasis (49).

A Potential Role of RORs in Xeno- and Endobiotic Gene Regulation
Both ROR{alpha} and ROR{gamma} have been shown to be expressed in the liver (58). However, the hepatic function of these two receptors remains unknown until recently. To determine the role of ROR{alpha} in the liver, we examined the gene expression profiles in livers of the ROR{alpha}sg/sg, ROR{gamma} null and ROR{alpha}sg/sg/ROR{gamma} double knockout (DKO) mice by microarray analysis (58). To our surprise, the microarray results suggested that loss of ROR{alpha} and/or ROR{gamma} had a major effect on the expression of multiple drug metabolizing enzymes and transporters (58). The effects of loss of ROR{alpha} are summarized in Table 2Go. In the ROR DKO mice, major effects on gene regulation include the activation of Cyp2b9/10, Cyp4a10 and Cy-p4a14, Sult1e1/Est and Sult2a9/2a1, and suppression of Cyp7b1, Cyp8b1, Hsd3b4, and Hsd3b5 (58). Interestingly, some genes are selectively controlled by ROR{alpha} or ROR{gamma}, whereas some other genes are affected by both receptors. For example, Hsd3b4 and Hsd3b5, two enzymes involved in the deactivation of steroid hormone, were decreased in both ROR{alpha}sg/sg and ROR{gamma} null mice, whereas the decreases of these genes in ROR DKO mice were more dramatic than those of single knockout mice (58).


View this table:
[in this window]
[in a new window]

  		Table 2. Summary of Major Regulation of Drug Metabolizing Enzymes in the ROR{alpha} Null Mice
 
Some of the gene regulation observed in the ROR loss of function knockout mouse models have been further supported by studies using ROR gain of function experiments. For example, we showed that overexpression of ROR{alpha} by transfection in primary mouse hepatocytes or mouse liver in vivo suppressed the expression of Sult1e1/Est and Sult2a9/2a1, consistent with the activation of the same genes in the ROR{alpha}sg/sg mice (58).

To study the mechanism by which RORs affect the expression of CYP genes, we focused on the regulation of oxysterol 7{alpha}-hydroxylase (Cyp7b1), an enzyme that plays an important role in the homeostasis of cholesterol, oxysterols and bile acids (59, 60). The expression of Cyp7b1 gene was suppressed in the ROR{alpha}sg/sg mice (58, 61), suggesting ROR{alpha} as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of ROR{alpha} and a functional RORE was identified in the Cyp7b1 gene promoter. Moreover, transfection of ROR{alpha} induced the expression of endogenous Cyp7b1 in the mouse liver. Interestingly, Cyp7b1 regulation appeared to be ROR{alpha}-specific, as ROR{gamma} had little effect, consistent with the notion that ROR{alpha}, but not ROR{gamma}, may play a dominating role in Phase I and Phase II enzyme regulation. Our microarray analysis also suggests that, although loss of ROR{gamma} alone affected the expression of some enzymes, the overall effect of ROR{gamma} null on metabolic enzyme regulation was not as dramatic as that observed in the ROR{alpha} null or ROR{alpha}/ROR{gamma} DKO mice (58). The molecular mechanism by which RORs affect the expression of other drug metabolizing enzymes remains to be established.

Although the primary focus of this article is the regulation of xeno- and endobiotic gene expression, it is worthwhile to mention that in addition to the regulation of drug metabolizing enzyme and transporter genes, loss of ROR{alpha} and/or ROR{gamma} also affect the expression of many other genes in the liver (for the complete microarray data, see http://www.ncbi.nlm.nih.gov/geo/ (GEO Series accession number GSE7564)). Moreover, ROR{alpha}sg/sg mice, but not the ROR{gamma} null mice, showed lower plasma triglyceride and cholesterol levels than the control mice. In contrast, ROR{gamma} null mice, but not ROR{alpha}sg/sg mice, exhibited lower blood glucose levels. These results suggested ROR{alpha} and ROR{gamma} may play distinct roles in the regulation of triglyceride and glucose homeostasis, respectively.

LXR and Its Regulation of Xeno- and Endobiotic Genes
LXRs, both the {alpha} and β isoforms (NR1H2, 3), were cloned and initially defined as sterol sensors that can be activated by the endogenous cholesterol derivative hydroxycholesterols, as well as synthetic LXR agonists, such as T0901317 (TO1317) and GW3965 (62, 63). Upon ligand activation, LXRs regulate gene expression by heterodimerization with the retinoid X receptor (RXR) and subsequent binding of LXR-RXR heterodimers to LXR response elements (LXREs) present in target gene promoters. LXR{alpha} is highly expressed in the liver and is also found in adipose, intestine, kidney and macrophages, whereas LXRβ is ubiquitously expressed (64, 65).

LXR was first shown to have an anti-atherosclerogenic effect by favoring an overall increase in cholesterol removal, while decreasing endogenous cholesterol synthesis and dietary absorption (65–67). Despite their promises as anti-atherosclerogenic targets, LXRs were linked to pro-lipogenic effects by activating the sterol regulatory element-binding protein-1c (SREBP-1c), a transcriptional factor that regulates the expression of a battery of lipogenic enzymes, including stearoyl CoA desaturase-1 (SCD-1), acetyl CoA carboxylase (ACC), and fatty acid synthase (FAS) (62, 68–70). In macrophages, activation of LXRs results in the efflux of cholesterol via the up-regulation of LXR target genes ABCA1, ABCG1, and ApoE (71). Treatment with LXR agonists in macrophages prevented bacterial or LPS-triggered induction of inflammatory signals. LXR signaling can impact antimicrobial responses by regulating macrophage gene expression and apoptosis (72, 73).

LXRs have been recently shown to regulate drug metabolizing enzymes, including sulfotransferases, suggesting a broader function of LXR beyond being sterol sensors. We have recently reported that LXRs can regulate Sult2a9/2a1 and impact sensitivity to bile acid toxicity and cholestasis (48). Genetic (using VP-LXR{alpha} transgene) or pharmacological (using a LXR agonist) activation of LXR in mice conferred a resistance to lithocholic acid (LCA)-induced hepatotoxicity and bile duct ligation (BDL)-induced cholestasis in female mice. In contrast, LXR DKO mice deficient of both the {alpha} and β isoforms exhibited heightened cholestatic sensitivity. LXR-mediated cholestatic resistance was associated with an increased expression of Sult2a9/2a1 and several bile acid transporters, whereas the basal expression of these gene products was reduced in the LXR DKO mice. In the same study, promoter analysis established Sult2a9/2a1 as a LXR target gene (48).

In another independent study, we showed that LXR controls estrogen homeostasis by regulating the basal and inducible hepatic expression of estrogen sulfotransferase (Est/Sult1e1), a designated sulfotransferase that catalyzes the sulfonation and deactivation of estrogens (74). Genetic or pharmacological activation of LXR resulted in Est/Sult1e1 induction, which in turn inhibited estrogen-dependent uterine epithelial cell proliferation and gene expression, as well as estrogen-dependent breast cancer growth in a nude mouse model of tumorigenicity. We further established that Est/Sult1e1 is a transcriptional target of LXR and a deletion of the Est/Sult1e1 gene in mice abolished the LXR effect on estrogen deprivation (49).

In addition to its regulation on SULTs, LXR may influence the expression of Phase I and Phase II enzymes other than SULTs. It was reported that loss of both LXR isoforms in mice resulted in an increased basal expression of Cyp3a11 and 2b10 (75). In contrast, activation of LXR resulted in a suppression of Cyp3a11 expression, but had little effect on the expression of Ugt1a1 (48).

A Functional Cross-Talk Between ROR{alpha} and LXR in the Regulation of Xeno- and Endobiotic Genes
The possibility of ROR{alpha}-LXR crosstalk was initially indicated by the remarkable overlap in the pattern of genes affected in livers from the ROR{alpha}sg/sg and LXR-activated mice. As mentioned earlier, activation of LXR in mice induced the expression of Est/Sult1e1 and Sult2a9/2a1. In the same LXR-activated mice, the expression of Cyp7b1 was suppressed (48), whereas the expression of CD36, a fatty acid uptake transporter, was induced (76). Remarkably, the same pattern of gene regulation was observed in the ROR{alpha}sg/sg mice. These results suggest that ROR{alpha} and LXR may be mutually suppressive in vivo.

To obtain support for this hypothesis, we examined the mutual suppression between ROR{alpha} and LXR using the regulation of Cyp7b1 as a model system. Having established ROR{alpha} as a positive Cyp7b1 regulator and knowing LXR suppresses the expression of Cyp7b1, we hypothesized that LXR may suppress Cyp7b1 gene expression by antagonizing ROR{alpha} activity. Indeed, we showed that the activation of Cyp7b1 promoter by ROR{alpha} was suppressed by co-transfection of LXR{alpha}, even in the absence of LXR agonists. The inhibitory effect of LXR{alpha} was enhanced by the LXR agonist TO1317. The inhibitory effect of LXR{alpha} was largely abolished when the RORE was mutated, suggesting that the inhibition was mediated by ROR{alpha} (61). The inhibitory effect of LXR on ROR was also seen when the RORE-containing synthetic reporter genes were used (61). The LXR{alpha} activity was reciprocally suppressed by ROR{alpha}. tk-MTV is a LXR-responsive reporter gene (77). We showed that the activation of tk-MTV by LXR{alpha} was inhibited by co-transfection of ROR{alpha} in a dose-dependent manner.

Our further studies suggest that, at least in cultured cells, the mutual suppression between ROR{alpha} and LXR may be due to their competition for the nuclear receptor co-activators. ROR{alpha} is known to interact with nuclear receptor co-activators without an exogenously added ligand (78, 79). We showed that LXR{alpha} also exhibited ligand-independent interaction with the nuclear receptor co-activator SRC-1 as confirmed by both mammalian two-hybrid assay and chromatin immunoprecipitation (ChIP) analysis. We hypothesize that the ligand-independent recruitment of co-activator accounts for the constitutive activities of both ROR{alpha} and LXR, and co-activator competition may represent a plausible mechanism for the mutual suppression of transcriptional activity between these two receptors. However, we cannot exclude the possibility that the "constitutive" activity of ROR{alpha} may have resulted from the binding of an endogenous ligand to this "orphan receptor".

The potential functional crosstalk between ROR{alpha} and LXR was further investigated in vivo. For this purpose, we measured the expression of LXR target genes and ROR target genes in the ROR{alpha}sg/sg and LXR DKO mice, respectively. As summarized in Table 3Go, in female ROR{alpha}sg/sg mice, in addition to the activation of Est/Sult1e1, Sult2a9/2a1, Cd36 and Cyp7b1, the expression of other LXR target genes, such as lipoprotein lipase (Lpl) (80), aldo-keto reductase 1d1 (Akr1d1) (81), scavenger receptor BI (SR-BI) (82) and acetyl CoA carboxylase 1 (Acc-1), was also significantly induced. However, the expression of Srebp-1c was significantly suppressed, whereas the expression of ApoE, Abcg5 and LXRs was not affected. When the expression of ROR{alpha} target genes was measured in the LXR DKO mice, we found that the expression of Bmal1 (83), ApoAI (26), p21 (84) and Ikkβ (29) was induced in LXR DKO female mice, but the expression of ApoCIII (85), Reverb{alpha} (78) and ROR{alpha} was not significantly altered as summarized in Table 4Go. It is interesting to note that the mutual activation of target gene expression in the ROR{alpha}sg/sg and LXR DKO mice are gene-specific. The mechanism for this selective gene regulation remains to be determined. Crosstalk between ROR{alpha} and LXR can involve several mechanisms, including competition for co-activators and DNA binding sites. In addition, the promoter context might be a determining factor. The inhibition of ROR{alpha}-mediated Cyp7b1 activation by LXR appears to involve competition for common co-activators. Repression of LXR target genes by ROR{alpha} may also be mediated through crosstalk involving adjacent or distant ROREs.


View this table:
[in this window]
[in a new window]

  		Table 3. Regulation of LXR Target Genes in Female ROR{alpha} Null Mice
 

View this table:
[in this window]
[in a new window]

  		Table 4. Regulation of ROR Target Genes in Female LXR DKO Mice
 
The activation of LXR target genes in the ROR{alpha}sg/sg mice has its physiological consequences. We showed that ROR{alpha}sg/sg mice exhibited an increase in hepatic triglyceride accumulation. The expression of Srebp-1c, a LXR target gene, however, was not induced in the ROR{alpha}sg/sg mice (61). We reason that the hepatic steatotic phenotype in ROR{alpha}sg/sg mice is most likely accounted by the activation of Cd36, another LXR target gene. Cd36, a fatty acid transporter, facilitates the uptake of free fatty acids from the circulation and their subsequent conversion into triglycerides. We have recently shown that the steatotic effect of both PXR (86) and LXR (76) was associated with the activation of Cd36. Moreover, the steatotic effect of LXR agonists was largely abolished in mice deficient of Cd36 (76). The LXR-ROR crosstalk and its potential implications in physiology are summarized in Figure 4Go.


Figure 4
View larger version (13K):
[in this window]
[in a new window]

  		Figure 4. Proposed model of ROR-LXR crosstalk and its potential implications in physiology.

 
Conclusions and Perspectives
Our recent findings have clearly suggested that RORs can positively or negatively regulate the expression of drug metabolizing enzymes in a gene specific manner. Although ROR{alpha} regulates the expression of certain drug metabolizing enzymes, it is questionable that ROR{alpha} is a traditional "xenobiotic receptor." Unlike PXR and CAR that are mostly associated with positive xenobiotic gene regulation, ROR{alpha} can exert both positive and negative regulation in a gene-specific manner. Another hallmark of xenobiotic receptors is their wide spectrum of xenobiotic ligands. Unlike their xenobiotic receptor counterparts, no physiological ROR agonists have been reported despite efforts from several laboratories (9, 12).

The crosstalk between ROR{alpha} and LXR is of particular interest. The crosstalk between xenobiotic receptors PXR and CAR has been reported and shown to involve competition for binding to the same DNA response elements and therefore regulation of common target genes (53). Nuclear receptors may also crosstalk in regulating xeno- and endobiotic genes through the presence of multiple nuclear receptor binding sites on the same target gene promoter. For example, we have recently shown that PXR, LXR and PPAR{gamma} cooperate to regulate the free fatty acid transporter CD36. In this case, three distinct nuclear receptor response elements, a DR3/PXRE, a DR7/LXRE and a DR1/PPRE, were found to cluster in 500-bp sequences of the mouse Cd36 gene promoter (76). The ROR{alpha}-LXR crosstalk appears to involve the competition of common co-activators, adding another dimension of complexity to the nuclear receptor-mediated metabolic safety net.

Although the role of RORs in xeno- and endobiotic gene regulation has emerged, there are several outstanding challenges. First, the physiological relevance of ROR-mediated xeno- and endobiotic gene regulation remains to be further defined. For example, the oxysterol levels were increased in mice deficient of Cyp7b1, presumably due to a defect in the conversion of oxysterols to bile acids (87). It would be interesting to know whether the decreased basal expression of Cyp7b1 in the ROR{alpha}sg/sg mice is associated with accumulation of oxysterols, the endogenous LXR agonists. It is also unknown whether the activation of Sult2a9/2a1 and Est/Sult1e1 in the ROR{alpha}sg/sg mice will be associated with decreased sensitivity to bile acid toxicity and compromised estrogen responses, respectively. Second, having established Cyp7b1 as a ROR{alpha} target gene, the molecular mechanism for the activation of Sult2a9/2a1 and Est/Sult1e1 in the ROR{alpha}sg/sg mice remains to be established. It would be interesting to determine whether RORs exert their effect on Sult2a9/2a1 and Est/Sult1e1 gene expression via crosstalk with LXR. Finally, continued effort should be made to identify or develop functional ROR ligands, which will provide valuable pharmacological tools to dissect the function of RORs.


   Footnotes
 
The original results from our labs described in this article were generated with the supported of NIH grants CA107011 and ES014626 (W.X.) and the Intramural Research Program of the NIEHS, NIH (A.M.J.).


   References
Top
 Abstract
 Introduction
 References
 

  1. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell 83:841–850, 1995.[CrossRef][Medline]
  2. Olefsky JM. Nuclear receptor minireview series. J Biol Chem 276: 36863–36864, 2001.[Free Full Text]
  3. Jetten AM, Kurebayashi S, Ueda E. The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res 69:205–247, 2001.[Medline]
  4. Carlberg C, Hooft van Huijsduijnen R, Staple JK, DeLamarter JF, Becker-Andre M. RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol Endocrinol 8:757–770, 1994.[Abstract/Free Full Text]
  5. Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, Russell LB, Mueller KL, van Berkel V, Birren BW, Kruglyak L, Lander ES. Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature 379:736–739, 1996.[CrossRef][Medline]
  6. Steinmayr M, Andre E, Conquet F, Rondi-Reig L, Delhaye-Bouchaud N, Auclair N, Daniel H, Crepel F, Mariani J, Sotelo C, Becker-Andre M. Staggerer phenotype in retinoid-related orphan receptor alpha-deficient mice. Proc Natl Acad Sci U S A 95:3960–3965, 1998.[Abstract/Free Full Text]
  7. Andre E, Gawlas K, Steinmayr M, Becker-Andre M. A novel isoform of the orphan nuclear receptor RORbeta is specifically expressed in pineal gland and retina. Gene 216:277–283, 1998.[CrossRef][Medline]
  8. Medvedev A, Yan ZH, Hirose T, Giquere V, Jetten AM. Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element. Gene 181:199–206, 1996.[CrossRef][Medline]
  9. Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, Fournier B. X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure (Camb) 10:1697–1707, 2002.[Medline]
  10. Missbach M, Jagher B, Sigg I, Nayeri S, Carlberg C, Wiesenberg I. Thiazolidine diones, specific ligands of the nuclear receptor retinoid Z receptor/retinoid acid receptor-related orphan receptor a with potent antiarthritic activity. J Biol Chem 271:13515–13522, 1998.
  11. Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C. Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand. Nucleic Acid Res 23:327–333, 1995.[Abstract/Free Full Text]
  12. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schule R. All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat Struct Biol 10:820–825, 2003.[CrossRef][Medline]
  13. Giguere V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev 8:538–553, 1994.[Abstract/Free Full Text]
  14. Harding HP, Atkins GB, Jaffe AB, Seo WJ, Lazar MA. Transcriptional activation and repression by RORalpha, an orphan nuclear receptor required for cerebellar development. Mol Endocrinol 11:1737–1746, 1997.[Abstract/Free Full Text]
  15. Atkins GB, Hu X, Guenther MG, Rachez C, Freedman LP, Lazar MA. Coactivators for the orphan nuclear receptor RORalpha. Mol Endocrinol 13:1550–1557, 1999.[Abstract/Free Full Text]
  16. Gold DA, Baek SH, Schork NJ, Rose DW, Larsen DD, Sachs BD, Rosenfeld MG, Hamilton BA. RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways. Neuron 40:1119–1131, 2003.[CrossRef][Medline]
  17. Jetten AM, Joo JH. Retinoid-related orphan receptors (RORs): roles in cellular differentiation and development. Adv Devel Biol 16:314–354, 2006.
  18. Liu C, Li S, Liu T, Borjigin J, Lin JD. Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature 447:447–481, 2007.[Medline]
  19. Jarvis CI, Staels B, Brugg B, Lemaigre-Dubreuil Y, Tedgui A, Mariani J. Age-related phenotypes in the staggerer mouse expand the RORalpha nuclear receptor’s role beyond the cerebellum. Mol Cell Endocrinol 186:1–5, 2002.[CrossRef][Medline]
  20. Jaradat M, Stapleton C, Tilley SL, Dixon D, Erikson CJ, McCaskill JG, Kang HS, Angers M, Liao G, Collins J, Grissom S, Jetten AM. Modulatory role for retinoid-related orphan receptor alpha in allergen-induced lung inflammation. Am J Respir Crit Care Med 174:1299–1309, 2006.[Abstract/Free Full Text]
  21. Stapleton CM, Jaradat M, Dixon D, Kang H.S, Kim SC, Liao G, Carey MA, Cristiano J, Moorman MP, Jetten AM. Enhanced susceptibility of Staggerer (ROR{alpha}sg/sg) mice to lipopolysaccharide-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 280:144–152, 2005.
  22. Akashi M, Takumi T. The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol 12:441–448, 2005.[CrossRef][Medline]
  23. Meyer T, Kneissel M, Mariani J, Fournier B. In vitro and in vivo evidence for orphan nuclear receptor RORalpha function in bone metabolism. Proc Natl Acad Sci U S A 97:9197–9202, 2000.[Abstract/Free Full Text]
  24. Lau P, Bailey P, Dowhan DH, Muscat GE. Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD. Nucleic Acids Res 27:411–420, 1999.[Abstract/Free Full Text]
  25. Besnard S, Bakouche J, Lemaigre-Dubreuil Y, Mariani J, Tedgui A, Henrion D. Smooth muscle dysfunction in registance arteries of the sg/sg mouse, a mutant of the nuclear receptor RORalpha. Cir Res 90: 820–825, 2002.[Abstract/Free Full Text]
  26. Vu-Dac N, Gervois P, Grotzinger T, De Vos P, Schoonjans K, Fruchart JC, Auwerx J, Mariani J, Tedgui A, Staels B. Transcriptional regulation of apolipoprotein A-I gene expression by the nuclear receptor RORalpha. J Biol Chem 272:22401–22404, 1997.[Abstract/Free Full Text]
  27. Besnard S, Heymes C, Merval R, Rodriguez M, Galizzi JP, Boutin JA, Mariani J, Tedgui A. Expression and regulation of the nuclear receptor RORalpha in human vascular cells. FEBS Lett 511:36–40, 2002.[CrossRef][Medline]
  28. Besnard S, Silvestre JS, Duriez M, Bakouche J, Lemaigre-Dubreuil Y, Mariani J, Levy BI, Tedgui A. Increased ischemia-induced angiogenesis in the sg/sg mouse, a mutant of the nuclear receptor RORalpha. Circ Res 89:1209–1215, 2001.[Abstract/Free Full Text]
  29. Delerive P, Monte D, Dubois G, Trottein F, Fruchart-Najib J, Mariani J, Fruchart JC, Staels B. The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response. EMBO Rep 2:42–48, 2001.[CrossRef][Medline]
  30. Andre E, Conquet F, Steinmayr M, Stratton SC, Becker-Andre M. Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J 17:3867–3877, 1998.[CrossRef][Medline]
  31. Srinivas M, Ng L, Liu H, Jia L, Forrest D. Activation of the blue opsin gene in cone photoreceptor development by retinoid-related orphan receptor beta. Mol Endocrinol 20:1728–1741, 2006.[Abstract/Free Full Text]
  32. Kurebayashi S, Ueda E, Sakaue M, Dhavalkumar D, Patel DD, Medvedev A, Feng Zhang F, Jetten AM. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A 97:10132–10137, 2000.[Abstract/Free Full Text]
  33. Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288:2369–2373, 2000.[Abstract/Free Full Text]
  34. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17(+) T helper cells. Cell 126:1121–1133, 2006.[CrossRef][Medline]
  35. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORalpha and RORgamma. Immunity 28: 29–39, 2008.[CrossRef][Medline]
  36. Sonoda J, Rosenfeld JM, Xu L, Evans RM, Xie W. A nuclear receptor-mediated xenobiotic response and its implication in drug metabolism and host protection. Curr Drug Metab 4:59–72, 2003.[CrossRef][Medline]
  37. Xie W, Uppal H, Saini SP, Mu Y, Little JM, Radominska-Pandya A, Zemaitis MA. Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism. Drug Discov Today 9:442–449, 2004.[CrossRef][Medline]
  38. 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 92:73–82, 1998.[CrossRef][Medline]
  39. Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES, Evans RM. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195–3205, 1998.[Abstract/Free Full Text]
  40. Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC, Neuschwander-Tetri BA, Brunt EM, Guzelian PS, Evans RM. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406:435–439, 2000.[CrossRef][Medline]
  41. 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 98:3369–3374, 2001.[Abstract/Free Full Text]
  42. Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 18:5652–5658, 1998.[Abstract/Free Full Text]
  43. Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407:920–923, 2000.[CrossRef][Medline]
  44. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, Mangelsdorf DJ. Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313–1316, 2002.[Abstract/Free Full Text]
  45. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403, 2001.[Abstract/Free Full Text]
  46. Ito O, YasuhiroNakamura Y, Tan L, Ishizuka T, Sasaki Y, Minami N, Kanazawa M, Ito S, Sasano H, Kohzuki M. Expression of cytochrome P-450 4 enzymes in the kidney and liver: regulation by PPAR and species-difference between rat and human. Mol Cell Biochem 10:141–148, 2006.
  47. Marschall HU, Wagner M, Bodin K, Zollner G, Fickert P, Gumhold J, Silbert D, Fuchsbichler A, Sjövall J, Trauner M. Fxr(–/–) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids. J Lipid Res 47:582–592, 2006.[Abstract/Free Full Text]
  48. Uppal H, Saini SP, Moschetta A, Mu Y, Zhou J, Gong H, Zhai Y, Ren S, Michalopoulos GK, Mangelsdorf DJ, Xie W. Activation of LXRs prevents bile acid toxicity and cholestasis in female mice. Hepatology 45:422–432, 2007.[CrossRef][Medline]
  49. Gong H, Guo P, Zhai Y, Zhou J, Uppal H, Jarzynka MJ, Song W, Cheng S, Xie W. Estrogen deprivation and inhibition of breast cancer growth in vivo through activation of the orphan nuclear receptor LXR. Mol Endocrinol 21:1781–1790, 2007.[Abstract/Free Full Text]
  50. Gonzalez FJ. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci 13:346–352, 1992.[CrossRef][Medline]
  51. Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R, Moore DD. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci U S A 100:4156–4161, 2003.[Abstract/Free Full Text]
  52. 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 100:4150–4155, 2003.[Abstract/Free Full Text]
  53. Saini SP, Mu Y, Gong H, Toma D, Uppal H, Ren S, Li S, Poloyac SM, Xie W. Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice. Hepatology 41:497–505, 2005.[CrossRef][Medline]
  54. 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 98:3375–3380, 2001.[Abstract/Free Full Text]
  55. Uppal H, Toma D, Saini SP, Ren S, Jones TJ, Xie W. Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice. Hepatology 41:168–176, 2005.[CrossRef][Medline]
  56. Zhang J, Huang W, Qatanani M, Evans RM, Moore DD. The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. J Biol Chem 279:49517–49522, 2004.[Abstract/Free Full Text]
  57. Stedman CA, Liddle C, Coulter SA, Sonoda J, Alvarez JG, Moore DD, Evans RM, Downes M. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci U S A 102:2063–2068, 2005.[Abstract/Free Full Text]
  58. Kang HS, Angers M, Beak JY, Wu X, Gimble JM, Wada T, Xie W, Collins JB, Grissom SF, Jetten AM. Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism. Physiol Genomics 31:281–294, 2007.[Abstract/Free Full Text]
  59. Schwarz M, Lund EG, Rusell DW. Two 7 alpha-hydroxylase enzymes in bile acid biosynthesis. Curr Opin Lipidol 9:113–118, 1998.[CrossRef][Medline]
  60. Chiang JY. Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J Hepatol 40:539–551, 2004.[CrossRef][Medline]
  61. Wada T, Kang HS, Angers M, Gong H, Bhatia S, Khadem S, Ren S, Ellis E, Strom S, Jetten A, Xie W. Identification of oxysterol 7{alpha}-hydroxylase (Cyp7b1) as a novel ROR{alpha} (NR1F1) target gene and a functional crosstalk between ROR{alpha} and LXR (NR1H3). Mol Pharmacol 73:891–899, 2008.[Abstract/Free Full Text]
  62. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B. Role of LXRs in control of lipogenesis. Genes Dev 14:2831–2838, 2000.[Abstract/Free Full Text]
  63. Collins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ, Wilson JG, Tippin TK, Binz JG, Plunket KD, Morgan DG, Beaudet EJ, Whitney KD, Kliewer SA, Willson TM. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 45:1963–1966, 2002.[CrossRef][Medline]
  64. Repa JJ, Mangelsdorf DJ. The liver X receptor gene team: potential new players in atherosclerosis. Nat Med 8:1243–1248, 2002.[CrossRef][Medline]
  65. Gong H, Xie W. Orphan nuclear receptors, PXR and LXR: new ligands and therapeutic potential. Expert Opin Ther Targets 8:49–54, 2004.[CrossRef][Medline]
  66. Millatt LJ, Bocher V, Fruchart JC, Steals B. Liver X receptors and the control of cholesterol homeostasis: potential therapeutic targets for the treatment of atherosclerosis. Biocheim Biophys Acta 1631:107–118, 2003.[Medline]
  67. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science 294:1866–1870, 2001.[Abstract/Free Full Text]
  68. Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 10:1096–1107, 1996.[Abstract/Free Full Text]
  69. Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, Gotoda T, Ishibashi S, Yamada N. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem 274:35840–35844, 1999.[Abstract/Free Full Text]
  70. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14:2819–2830, 2000.[Abstract/Free Full Text]
  71. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289:1524–1529, 2000.[Abstract/Free Full Text]
  72. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 9:213–219, 2203.
  73. Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hongenesch J, O’Connell RM, Cheng G, Miller JF, Tontonoz P. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119:299–309, 2004.[CrossRef][Medline]
  74. Song WC. Biochemistry and reproductive endocrinology of estrogen sulfotransferase. Ann N Y Acad Sci 948:43–50, 2001.[CrossRef][Medline]
  75. Gnerre C, Schuster GU, Roth A, Handschin C, Johansson L, Looser R, Parini P, Podvinec M, Robertsson K, Gustafsson JA, Meyer UA. LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver. J Lipid Res 46:1633–1642, 2005.[Abstract/Free Full Text]
  76. 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 PPAR{gamma} in promoting steatosis. Gastroenterology 134:556–567, 2008.[Medline]
  77. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Gene Dev 9:1033–1045, 1995.[Abstract/Free Full Text]
  78. Delerive P, Chin WW, Suen CS. Identification of Reverb (alpha) as a novel ROR(alpha) target gene. J Biol Chem 277:35013–35018, 2002.[Abstract/Free Full Text]
  79. Kurebayashi S, Nakajima T, Kim SC, Chang CY, McDonnell DP, Renaud JP, Jetten AM. Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma. Biochem Biophys Res Commun 315:919–927, 2004.[CrossRef][Medline]
  80. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ. Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta. J Biol Chem 276:43018–43024, 2001.[Abstract/Free Full Text]
  81. Volle DH, Repa JJ, Mazur A, Cummins CL, Val P, Henry-Berger J, Caira F, Veyssiere G, Mangelsdorf DJ, Lobaccaro JM. Regulation of the aldo-keto reductase gene akr1b7 by the nuclear oxysterol receptor LXRalpha (liver X receptor-alpha) in the mouse intestine: putative role of LXRs in lipid detoxification processes. Mol Endocrinol 18:888–898, 2004.[Abstract/Free Full Text]
  82. Malerod L, Juvet LK, Hanssen-Bauer A, Eskild W, Berg T. Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochem Biophys Res Commun 299: 916–923, 2002.[CrossRef][Medline]
  83. Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43:527–537, 2004.[CrossRef][Medline]
  84. Schrader M, Danielsson C, Wiesenberg I, Carlberg C. Identification of natural monomeric response elements of the nuclear receptor RZR/ROR. They also bind COUP-TF homodimers. J Biol Chem 271:19732–19736, 1996.[Abstract/Free Full Text]
  85. Raspe E, Duez H, Gervois P, Fievet C, Fruchart JC, Bensnard S, Mariani J, Tedgui A, Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha. J Biol Chem 276:2865–2871, 2001.[Abstract/Free Full Text]
  86. 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 281:15013–15020, 2006.[Abstract/Free Full Text]
  87. Li-Hawkins J, Lund EG, Turley SD, Russell DW. Disruption of the oxysterol 7alpha-hydroxylase gene in mice. J Biol Chem 275:16536–16542, 2000.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
233/10/1191    most recent
0802-MR-50v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wada, T.
Right arrow Articles by Xie, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wada, T.
Right arrow Articles by Xie, W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS