Functional crosstalk of CAR–LXR and ROR–LXR in drug metabolism and lipid metabolism

Advanced Drug Delivery Reviews 62 (2010) 1316–1321

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Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r

Functional crosstalk of CAR–LXR and ROR–LXR in drug metabolism and lipid metabolism☆ Lei Xiao, Xinni Xie, Yonggong Zhai ⁎ Key Laboratory for Cell Proliferation and Regulation Biology, Ministry of Education, Biomedicine Research Institute and College of Life Sciences, Beijing Normal University, Beijing 100875, China

a r t i c l e

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Article history: Received 11 February 2010 Accepted 19 July 2010 Available online 24 July 2010 Keywords: Nuclear receptor LXR CAR ROR Drug metabolism Lipid metabolism Gene regulation

a b s t r a c t Nuclear receptor crosstalk represents an important mechanism to expand the functions of individual receptors. The liver X receptors (LXR, NR1H2/3), both the α and β isoforms, are nuclear receptors that can be activated by the endogenous oxysterols and other synthetic agonists. LXRs function as cholesterol sensors, which protect mammals from cholesterol overload. LXRs have been shown to regulate the expression of a battery of metabolic genes, especially those involved in lipid metabolism. LXRs have recently been suggested to play a novel role in the regulation of drug metabolism. The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic receptor that regulates the expression of drug-metabolizing enzymes and transporters. Disruption of CAR alters sensitivity to toxins, increasing or decreasing it depending on the compounds. More recently, additional roles for CAR have been discovered. These include the involvement of CAR in lipid metabolism. Mechanistically, CAR forms an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the LXRs, in exerting its effect on lipid metabolism. Retinoid-related orphan receptors (RORs, NR1F1/2/3) have three isoforms, α, β and γ. Recent reports have shown that loss of RORα and/or RORγ can positively or negatively influence the expression of multiple drug-metabolizing enzymes and transporters in the liver. The effects of RORs on expression of drug-metabolizing enzymes were reasoned to be, at least in part, due to the crosstalk with LXR. This review focuses on the CAR–LXR and ROR–LXR crosstalk, and the implications of this crosstalk in drug metabolism and lipid metabolism. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . LXR, CAR and ROR, and their cloning and initial characterizations. . . . 2.1. The sterol sensors LXRs . . . . . . . . . . . . . . . . . . . 2.2. The xenobiotic receptor CAR . . . . . . . . . . . . . . . . . 2.3. The orphan nuclear receptors RORs . . . . . . . . . . . . . . 3. Crosstalk of RORs and LXRs in lipid metabolism . . . . . . . . . . . 4. Crosstalk of CAR and LXRs links drug metabolism and lipid metabolism 5. Conclusion remarks . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Development of Novel Therapeutic Strategy by Regulating the Nuclear Hormone Receptors”. ⁎ Corresponding author. Tel.: +86 10 58806656; fax: +86 10 58807720. E-mail addresses: [email protected], [email protected] (Y. Zhai). 0169-409X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2010.07.006

The liver is an essential organ in metabolic homeostasis. Metabolic homeostasis includes those of the foreign substances or xenobiotics, as well as those of the endogenous chemicals or endobiotics. Xenobiotic homeostasis represents mammals' responses to xenobiotics, such as drugs and other obnoxious substances; whereas endobiotic homeostasis is the balanced production and elimination

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of endobiotics, such as lipids [1,2]. Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic compounds. The superfamily of cytochromes P450 (CYPs) enzymes is the best studied class of enzymes in this task [3]. Lipids are essential for energy homeostasis, reproductive and organ physiology, and numerous aspects of cellular biology. Disruption of lipid metabolism in the liver might trigger various metabolic diseases, such as atherosclerosis, diabetes and obesity. Nuclear receptors, a family of ligand-dependent transcriptional factors, play important roles in metabolic homeostasis. Most nuclear receptors contain an N-terminal DNA biding domain (DBD) and a Cterminal ligand binding domain (LBD). Nuclear receptors regulate gene expression by binding to their responsive elements present in target gene promoters. The nuclear receptor superfamily includes not only the classic endocrine receptors that mediate the actions of steroid hormones, thyroid hormones, and the fat-soluble vitamins A and D [4], but also a large number of so-called orphan nuclear receptors, whose ligands and physiological functions were initially unknown [5]. Over the last several years, many studies have elucidated the role of these orphan receptors in physiology and diseases. Among orphan receptors, it has been recognized that LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. RORs are known to play a role in tissue development, immune responses, and circadian rhythm. More recent reports suggested that in addition to their traditional functions, LXR, CAR and ROR can also impact other physiological pathways by crosstalking with each other. Specifically, LXR–CAR and ROR–LXR are found to be mutually suppressive, so these receptors can affect each others' activity and consequently affect the downstream events controlled by these receptors. This review will focus on the novel function of the crosstalk between RORs and LXRs and the crosstalk between CARs and LXRs in drug metabolism and lipid metabolism. 2. LXR, CAR and ROR, and their cloning and initial characterizations 2.1. The sterol sensors LXRs LXR was initially isolated from a human liver cDNA library as an orphan receptor [6]. There are two LXR isoforms in mammals, named LXRα (NR1H3) and LXRβ (NR1H2). High expression of LXRα is restricted to spleen, liver, adipose tissue, intestine, kidney and lung, whereas LXRβ is expressed in all tissues examined [6–9]. Both LXRα and LXRβ function as heterodimers with the retinoid X receptor (RXR). The LXR/RXR heterodimers preferentially bind to LXR response element (LXRE) that consists of two hexanucleotide repeats separated by 4 nucleotides (i.e. DR4). The most potent endogenous activators of LXRs are 22(R)-hydroxycholesterol and 20(S)-hydroxycholesterol, 24 (S)-hydroxycholesterol and 24(S), 25-epoxycholesterol [10–13]. In addition to natural ligands, a number of potent synthetic LXR agonists, such as T0901317 and GW3965 [14,15] have also been developed. The activity of LXR is regulated not only by agonists, but also by changes in receptor expression [16]. LXRs act as sterol sensors, protecting the cells from cholesterol overload by stimulating reverse cholesterol transport and activating its conversion to bile acids in the liver. In rodents, LXRs increase hepatic cholesterol catabolism by inducing the rate-limiting enzyme cholesterol 7α-hydroxylase (Cyp7a1) that catalyzes the conversion of cholesterol to bile acids [17]. LXRs were later found to promote hepatic lipogenesis by activating sterol regulatory element-binding protein 1c (SREBP-1c) and its target genes including acetyl-CoA carboxylase-1 (ACC-1), fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1) [18,19]. In addition to being regulated by SREBP-1c, ACC-1, FAS and SCD-1 have also been shown to be the direct transcriptional targets of LXRs [20–22].

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Recently, some other LXR target genes have been identified. These include the bile acid-detoxifying sulfotransferase (Sult2a9/2a1) [23], estrogen sulfotransferase (Est/Sult1e1) [24], and fatty acid transporter (Cd36). The activation of Sult2a9/2a1 by LXR was associated with increased bile acid detoxification and alleviation of cholestasis [25]. In the same study, the expression of Cyp7b1 was found to be suppressed in LXR-activated mice [25]. Activation of Est/Sult1e1 by LXR led to functional estrogen deprivation and inhibition of estrogen-dependent breast cancer growth [25]. More recently, Cd36 has been shown to be an LXR target gene and an intact expression of Cd36 plays an important role in the steatotic effect of LXR agonists. It was recently reported that the loss of both LXR isoforms in mice resulted in increased basal expression of Cyp3a11 and 2b10 [26], two most abundantly expressed drug-metabolizing enzymes and primary target genes of xenobiotic receptors CAR and pregnane X receptor (PXR). However, the mechanism by which LXRs affect the expression of CYP enzymes remains largely unknown. 2.2. The xenobiotic receptor CAR CAR (NR1I3) belongs to a subgroup of nuclear receptors that include the vitamin D receptor (VDR), farnesoid X receptor (FXR), and LXR [27]. CAR serves as a key regulator of the body's response to xenobiotic and endobiotic stress. CAR is expressed primarily in the liver, intestine and kidney, also with some expression being detected in the heart and brain [28,29]. CAR, also a receptor that needs RXR to function, induces the metabolism of xenobiotics, bilirubin, and thyroid hormone. Unlike many other ligand-dependent nuclear receptors, CAR exhibits substantial constitutively active [28,29]. The constitutive activity of CAR was thought to be due to the ligand independent recruitment of nuclear receptor coactivators by CAR [30]. CAR can also be activated by a variety of compounds that include phenobarbital (PB), androstane steroidal compounds (i.e. 3α, 5αandrostanol), 5α-pregnane-3,20-dione, retinoic acids, clotrimazole, chlorpromazine (CPZ), o,p′-DDT, methoxychlor, and tohydrocarbons such as 2,3,3′,4′,5′,6-hexachlorobiphenyl,6-(4-chlorophenyl) imidazo [2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) [31–34]. Activation of CAR induces the expression of CYP enzymes and other gene products involved in the metabolism and excretion of xenobiotics, which in some instances, can cause dangerous drug–drug interactions [32]. Mice deficient of CAR had defective basal and inducible expression of xenobiotic enzymes and exhibited altered responses to xenobiotics, such as zoxazolamine, caffeine, and acetaminophen [35,36]. CAR regulates genes associated with drug elimination pathways including CYP2B, UDP-glucuronosyltransferase 1A1 (UGT1A1), and multidrug-resistance associated protein 2 (MRP2). In this signaling paradigm, the translocation of CAR into the nucleus serves as an important step to regulate the activity of CAR. CAR also regulates bilirubin metabolism and is, thus, an exciting therapeutic target for the treatment of neonatal jaundice. In addition to its xenobiotic function, CAR has recently been suggested to play an endobiotic role in energy metabolism, ranging from thyroid hormone metabolism and calorie restriction response [37,38] to lipogenesis [39–41]. CAR might also regulate energy metabolism by interacting with the peroxisome proliferators activated receptor α (PPARα) and PPARγ coactivator-1α (PGC-1α), both of which are key regulators of adaptive responses to starvation [42,43]. 2.3. The orphan nuclear receptors RORs Retinoid-related orphan receptors (RORs) include three isoforms: RORα (NR1F1), RORβ (NR1F2) and RORγ (NR1F3) [44]. Each ROR isoform has a distinct pattern of tissue distribution [45]. RORα is expressed in many tissues, including cerebellar Purkinje cells, liver,

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thymus, skeletal muscle, skin, lung and kidney [46,47]. RORβ exhibits a more restricted pattern of expression and is expressed in several regions of the central nervous system, retina, and pineal gland. RORγ is most highly expressed in thymus but also detectable in many other tissues, including liver, kidney and muscle [44,48,49]. The functional ligands of RORs remain elusive. It was reported that cholesterol and its sulfonated derivatives might function as RORα ligands [50]. Other ligands suggested to bind to RORα are melatonin and thiazolidinediones [51]. Evidence has been provided indicating that certain retinoids, including all-trans retinoic acid, can function as partial antagonists for RORβ and RORγ [52]. RORs bind 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 [53]. However, RORα has been suggested to bind as homodimers to direct repeats of the consensus AGGTCA motif separated by two base pairs (DR2) [54]. The transcriptional activities of RORs are negatively and positively regulated through the recruitment of nuclear receptor co-repressors and coactivators, respectively. It has been reported that co-repressors (N-CoR, RIP140 and SMRT) and coactivator (GRIP, PBP, SRC1, CBP and PGC-1α) can interact with RORα [55–58]. It was proposed that cellspecific interactions with specific co-regulators may contribute to the molecular mechanism for distinct physiological functions of RORα [54]. Characterizations of ROR null mice have revealed a number of important physiological functions of RORs. RORα−/−, RORβ−/− and RORγ−/− mice show some phenotypes in the vascular system. RORα is involved in postischemic angiogenesis and differentiation and contractile function of smooth muscle cells [56]. Meanwhile, RORα can act as a potent negative regulator of ischemia-induced angiogenesis. The effect of RORα on inflammation is a complex issue. RORα has been shown to enhance IkB expression thereby inhibiting NF-kB (in vitro studies), whereas in vivo RORαsg/sg mice are less sensitive to autoimmune and allergy-induced inflammation. This may be in part related to changes in thymocyte populations. Among other ROR isoforms, RORβ is believed to be involved in the processing of sensory information. RORβ has been reported to regulate the blue opsin gene in cone photoreceptor development [59]. RORγ plays an essential role in lymphoid organogenesis and thymopoiesis. Recent studies have also demonstrated an important role for both RORα and RORγ in the differentiation of naive T cells into Th17 cells [60,61]. Recently published results have also implicated RORα in the regulation of several lipid metabolism genes, thereby playing a role in circadian rhythm maintenance and plasma lipid control [62]. RORα also plays a role in muscle lipid metabolism [63], and controls the expression of the gluconeogenic gene glucose-6-phosphatase [64]. 3. Crosstalk of RORs and LXRs in lipid metabolism As discussed earlier, RORs and LXRs were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis [65]. The RORα–LXR crosstalk in lipid metabolism was initially suggested by the remarkable overlap in the pattern of genes affected in livers from the RORα null mice and LXR-activated mice. Activation of LXR in mice induced the expression of Est/Sult1e1, Sult2a9/2a1 and the fatty acid translocase Cd36, whereas the expression of Cyp7b1 was suppressed in LXR-activated mice [23]. Cyp7b1 is an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. Remarkably, the same pattern of gene regulation was observed in the RORαsg/sg mice that carry a natural loss of function mutation of RORα. The functional crosstalk between RORα and LXR was further investigated in vivo by measuring the expression of LXR target genes and ROR target genes in the RORαsg/sg and LXR DKO mice, respectively [66]. In female RORαsg/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) [67], aldo-keto reductase 1d1 (Akr1d1) [68], scavenger receptor BI (SR-BI) [69] and acetyl-CoA carboxylase 1 (Acc-1), was also significantly induced. However, the expression of several other LXR target genes, including Srebp-1c, ApoE, Abcg5, was not induced in RORαsg/sg mice. When the expression of RORα target genes was measured in LXR DKO mice, it was found that the expression of ROR target genes Bmal1 [70], ApoA1 [71], and Ikkβ [72] was induced in LXR DKO female mice, but the expression of ApoCIII [73], Rev-erbα [74] and RORα was not significantly altered. It is interesting to note that the mutual activation of target gene expression in the RORαsg/sg and LXR DKO mice is genespecific. The mechanism for this selective gene regulation remains to be determined. Crosstalk between RORα and LXR can involve several mechanisms, including competition for coactivators and DNA binding sites. In addition, the promoter context might be a determining factor. The inhibition of RORα-mediated Cyp7b1 activation by LXR appears to involve competition for common coactivators [66]. The activation of LXR target genes in the RORαsg/sg mice has its physiological consequences. It was reported that RORαsg/sg mice exhibited an increase in hepatic triglyceride accumulation, consistent with the activation of several LXR target lipogenic genes, as well as the induction of Cd36, a fatty acid translocase that facilitates the uptake of free fatty acids from the circulation and their subsequent conversion into triglycerides. In conclusion, the mutual suppression between RORα and LXR was supported by the in vivo observation that loss of RORα increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Reciprocally, mice deficient of LXR α and β isoforms showed activation of selected RORα target genes. Together, these results have suggested a novel role for RORα and a functional interplay between RORα and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis. 4. Crosstalk of CAR and LXRs links drug metabolism and lipid metabolism LXR and CAR are two nuclear receptors postulated to have distinct functions. LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. We have recently shown that LXRα and CAR are functionally related in vivo. Specifically, loss of CAR increased the expression of lipogenic LXR target genes, leading to increased hepatic triglyceride accumulation; whereas activation of CAR inhibited the expression of LXR target genes and LXR ligand-induced lipogenesis. Conversely, loss of LXRα and LXRβ increased the basal expression of xenobiotic CAR target genes, which is consistent with a recent report that loss of both LXR isoforms in mice resulted in increased basal expression of Cyp3a11 and 2b10 [26], two most abundantly expressed drug-metabolizing enzymes and primary target genes of xenobiotic receptors CAR and PXR. In contrast, activation of LXR inhibited the expression of CAR target genes and sensitized mice to xenobiotic toxicants, such as tribromoenthanol. The mutual suppression between LXRα and CAR was also observed in cell culture and reporter gene assays. LXRα, like CAR, exhibited constitutive activity in the absence of an exogenously added ligand by recruiting nuclear receptor coactivators. Interestingly, although CAR can compete with LXRα for coactivators, the constitutive activity and recruitment of coactivators was not required for CAR to suppress the activity of LXRα. In vivo chromatin immunoprecipitation (ChIP) assay showed that cotreatment of a CAR agonist compromised LXR agonist responsive recruitment of LXRα to Srebp-1c, whereas a LXR agonist inhibited CAR agonist responsive recruitment of CAR to Cyp2b10. Together, these results have suggested dual functions of LXRα and CAR in lipogenesis and xenobiotic responses, establishing a unique role of these two receptors in integrating xenobiotic and endobiotic homeostasis.

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Fig. 1. Proposed model of the crosstalks of ROR–LXR and CAR–LXR and their potential implications in physiology.

Based on our results, we propose a model of receptor crosstalk, in which the activation of LXRs suppresses CARs mediated xenobiotic response, leading to sensitization of animals to xenotoxicants. In contrast, activation of CAR suppresses the LXR mediated lipogenesis. The constitutive activity of LXRα and consequent suppression of CAR activity may have offered a mechanism of “checks and balances” to maintain an appropriate level of metabolic capacity in the hepatointestinal axis. 5. Conclusion remarks Recent findings from many laboratories have clearly suggested that nuclear receptors LXR, CAR and ROR not only have their “traditional” functions, but also have interesting crosstalk in their participation of drug metabolism and lipid metabolism. The crosstalk of ROR-LXR and CAR-LXR and their potential implications in physiology are summarized in Fig. 1. The crosstalk among these receptors has implications in drug development and pathophysiology. For example, having known that sustained activated of LXR may compromise drug metabolism, cautions to avoid drug accumulation and toxicity should be applied when LXR is being explored as a therapeutic target. On the other hand, deficiencies in LXR expression and/or activation may lead to the over-activation of xenobiotic responses which might lead to drug–drug interactions. In the case of CAR, it was recently reported that activation of CAR and subsequent inhibition of lipogenesis play an important role in the anti-obesity and anti-diabetes function of CAR [75]. It is tempting to speculate that CAR may represent a novel therapeutic target to manage obesity and diabetes. It is encouraging to note that CARactivating activities have been found not only in clinical drugs, but also in neutraceuticals such as herbal medicines [76], raising the hope that CAR could be a target for neutraceutical prevention and relief of metabolic syndrome. The ROR–LXR crosstalk is equally interestingly. The direction and extent of crosstalk can be shifted by the activation or inhibition of either receptor. Unlike many other nuclear receptors, no physiological ROR agonists have been reported despite efforts from several laboratories [50]. Therefore, continued effort should be made to identify or develop functional ROR ligands, which will provide valuable pharmacological tools to dissect the function of RORs. Acknowledgement This work was supported by grants (30870926 to Y.Z.) from the National Natural Science Foundation of China, grants from the CSCSE (2009), Key Laboratory of Beijing Normal University (2009), and Key

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