Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Abstract

Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

“…adopted orphan NRs have recently been found to be involved in xenobiotic and in lipid sensing (Chan et al, 2013;Chawla, Repa, Evans, & Mangelsdorf, 2001;Handschin & Meyer, 2005;Klaassen & Aleksunes, 2010;Wang & LeCluyse, 2003).…”

“…The xenosensors CAR (constitutive androstane receptor) and PXR/SXR (pregnane X receptor/steroid xenobiotic receptor) can also interact with lipid ligands (Chawla et al, 2001;Evans & Mangelsdorf, 2014;Handschin & Meyer, 2005;Ory, 2004). These NRs must heterodimerize with RXR (retinoid X receptor) to exert their gene regulatory function.…”

“…Lipid-and xenobiotic-sensing NRs have been implicated in the orchestrated transcriptional regulation of enzymes and transporters involved in lipid metabolism or detoxification and thus their action provides a coordinated cellular response to perturbations affecting these processes (Fig. 3) (Chan et al, 2013;Chawla et al, 2001;Handschin & Meyer, 2005;Jonker et al, 2009;Ory, 2004;Urquhart, Tirona, & Kim, 2007). Professional lipid ABC transporters, such as the cholesterol and phospholipid transporter ABCA1, the long-chain PC and cholesterol transporter ABCB4 (MDR3), the bile salt transporter ABCB11 (BSEP/S-P-gp), or the major sterol transporters ABCG5/G8 (working as an obligate heterodimer), have indeed been shown to be regulated by lipid-sensing NRs (Beyea et al, 2007;Jonker et al, 2009;Schmitz & Langmann, 2005;Tarling et al, 2013;van Meer et al, 2008).…”

“…s0060 3.4. Role of NRs in lipid metabolism and a potential indirect effect on ABCB1 and ABCG2 transporter function p0315 As mentioned above, NRs participate in the coordinated regulation of transcriptional programs which can influence overall lipid metabolism (Chawla et al, 2001;Handschin & Meyer, 2005;Ory, 2004). As detailed in the sections above…”

DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression

“…We further investigated T-DMRs in other liver-enriched transcription factors that support liver-specific gene expression (Giguere 1999;Handschin and Meyer 2005). In the cases of Nr1h3 (Lxr) and Nr1i2 (Pregnane X receptor, Pxr), the T-DMRs in The DAVID column indicates the overrepresentation of the terms in DAVID 2007 analysis among all genes classified into the same criterion according to the position of CGIs.…”