LXRs;: Oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis
Introduction
Analyses of the human genome indicate that there are at least 48 members of the nuclear hormone receptor superfamily (Committee, 1999). Each member of this large family of proteins controls transcription of a small set of target genes, often in response to small lipophilic ligands that bind to and alter the activation state of the receptor. Nuclear receptors have been broadly subdivided into steroid and nonsteroid receptors (Mangelsdorf et al., 1995). There are 12 steroid receptors, such as the estrogen and androgen receptors, that bind to DNA as homodimers. In contrast, many of the 36 nonsteroidal nuclear receptors, which include Liver X Receptor (LXR), farnesoid X-activated receptor (FXR), peroxisome proliferator-activated receptor (PPAR) and vitamin D3 receptor (VDR), form functional heterodimers with RXR and activate transcription in response to ligands for one or both nuclear receptor(s) (Fig. 1A–C; see below). Most nuclear receptors bind to specific cis elements called hormone response elements (HREs) that are located in the proximal promoter, distal enhancers or introns of target genes Edwards et al., 2002, Kast et al., 2001, Mangelsdorf and Evans, 1995, Zhang et al., 2001a.
LXRα was first cloned in 1995 using low stringency screening of a human liver library (Willy et al., 1995). The LXRα mRNA exhibited a specific pattern of expression that was limited to the visceral organs, intestine, liver, kidney and spleen (Willy et al., 1995). The highest mRNA expression was in the liver, hence the name LXR (Willy et al., 1995). Prior to 1995, RXR had been considered to function as a silent partner for members of the nonsteroidal nuclear receptor family. However, studies with the LXR/RXR heterodimer provided the first compelling evidence that RXR could function as a ligand-activated partner of some nuclear receptors (Willy et al., 1995). Subsequently, it has been shown that RXR functions as an active partner when dimerized with a number of other nuclear receptors, which include FXR, PPAR, PXR and VDR. The expression of the human LXRα gene was recently shown to be autoregulated by activated LXRα through a process that is dependent upon the LXR response element (LXRE) in the proximal promoter of the LXRα gene Laffitte et al., 2001a, Whitney et al., 2001.
LXRβ was cloned by four separate research groups and originally referred to as RIP-15 (Seol et al., 1995), OR1 (Teboul et al., 1995), NER (Shinar et al., 1994) or UR (Song et al., 1994). The DNA-binding domains and ligand-binding domains of LXRβ and LXRα have 77% identity at the amino acid level (Teboul et al., 1995). However, in contrast to LXRα, LXRβ is constitutively expressed at low levels in all tissues (Repa and Mangelsdorf, 2000). LXRα/ RXRα and LXRβ/RXRα heterodimers bind to an LXRE that is a variant of the idealized sequence AGGTCA N4 AGGTCA, a direct repeat separated by four nucleotides (DR-4). Analysis of the functional LXREs that have been characterized in the known LXR target genes indicates that the consensus LXRE contains a number of invariant nucleotides in each half site, and that the nucleotides at other positions can vary considerably (Fig. 2). Although LXRα and LXRβ both bind with similar affinities to idealized DR-4 elements, it is likely that these two nuclear receptors have differential effects on certain target genes (see below).
Based on original studies on the thyroid hormone receptor heterodimer (TR/RXR), a three-step transcriptional process for activation of nuclear hormone target genes was proposed (Wong et al., 1995) and reviewed in Glass et al. (1997). As discussed below, data derived from studies using wild-type and LXR null mice indicate that a similar model of transcriptional regulation may be valid for LXR/RXR (Fig. 1A–C). In this model, Fig. 1A represents the repressed transcriptional state that is envisaged to occur when corepressors are bound to LXR/RXR in the absence of ligand. However, a basal rate of transcription occurs when the corepressors start to dissociate from the LXR/RXR heterodimer in response to the initial binding of agonists to either LXR or RXR (Fig. 1B). Finally, transcription of the target gene is fully activated as coactivators are recruited to the ligand-activated LXR/RXR heterodimer (Fig. 1C). The model predicts that the mRNA levels of LXR target genes will be low in wild-type cells that are not exposed to LXR agonists (Fig. 1A), and high when the cells are treated with activators of LXR and/or RXR (Fig. 1C). The model also predicts that deletion of both LXR genes will prevent the formation of both the repressed and activated transcriptional states (Fig. 1). In addition, the model would suggest that in LXR null mice, mRNA levels of LXR target genes will be (i) intermediate between the repressed and activated levels noted in wild-type mice, and (ii) unaffected following treatment with agonists for LXR or RXR. Evidence supporting these predictions have been borne out in studies on the regulation of mRNAs encoding ABCG1 (Venkateswaran et al., 2000) (Fig. 1D), ABCA1 (Repa et al., 2000b), apolipoprotein E (ApoE) (Laffitte et al., 2001b) and sterol response element-binding protein (SREBP)-1c (Repa et al., 2000a). Detailed reviews on the roles of (i) corepressors and coactivators, (ii) acetylation and deacetylation of histones, and (iii) other DNA-associated proteins on transcription are available Glass and Rosenfeld, 2000, Glass et al., 1997, Lee and Kraus, 2001, Lemon and Freedman, 1999, Rosenfeld and Glass, 2001.
Section snippets
LXR: the oxysterol receptor
The original identification of oxysterols as natural ligands for LXR was reported almost simultaneously by three laboratories Forman et al., 1997, Janowski et al., 1996, Lehmann et al., 1997. These publications linked LXR to a physiological function. In one approach, Janowski et al. (1996) screened lipid extracts from various tissues and identified a class of meiosis-activating sterols as activators of an LXRE-controlled reporter gene. They also tested over 70 sterol derivatives and identified
LXR null mice
The generation of LXRα−/−, LXRβ−/− and LXRα/β−/− mice Alberti et al., 2001, Peet et al., 1998b has provided a critically important resource. Such mice are viable, fertile and show no aberrant phenotype when fed a regular chow diet, which contains relatively little cholesterol (0.02% wt/wt) (Peet et al., 1998b). Wild-type or LXRβ−/− mice are also relatively unaffected when they are fed a cholesterol-rich diet Alberti et al., 2001, Peet et al., 1998b. In contrast, administration of
LXR target genes: to activate or not to activate
At the present time, a relatively small number of LXR target genes have been identified (Fig. 2). With the exception of ABCG4, ABCG5 and ABCG8, one or more functional LXREs have been identified in the promoter, enhancer or intron of each of these genes. These LXR target genes encode proteins that have critical roles in regulating either the catabolism of cholesterol to bile acids (murine CYP7A1), the synthesis of fatty acids from precursors (SREBP-1c and fatty acid synthase, FAS), the
Conclusion
A number of drugs including statins, bile acid sequestrants, niacin and fibrates are currently prescribed to treat patients with different types of hyperlipidemias. Despite the reduction in plasma cholesterol and/or triglyceride concentrations and the reduced incidence of myocardiac infarcts following such treatment, it is clear that many patients either do not respond or are still at risk for coronary artery disease. Thus, there remains a significant need for additional modes of intervention
Acknowledgements
This work was supported by grants from the National Institutes of Health (HL 30568 and HL 68445), the Laubisch fund and the American Heart Association (0105381N) to P.A.E. M.A.K. was supported by a postdoctoral fellowship from the National Institutes of Health. P.A.M. was supported by a predoctoral fellowship from the American Heart Association (Western States affiliate). We thank the members of the Edwards Laboratory for critically reading the manuscript.
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2021, BoneCitation Excerpt :On the other hand, excessive accumulation of oxysterols and desmosterol, intermediate precursors in cholesterol biosynthesis, induces liver X receptors (LXRs) activation leading to direct activation of genes involved in the cholesterol efflux pathway, such as ATP-binding cassette (ABC) transporter A1 (ABCA1) and G1 (ABCG1). ABCA1 and ABCG1 then efflux excess cholesterol to HDL particles and apolipoprotein A1 (ApoA1) completing the mechanism by which the cellular cholesterol is eliminated from cells [93–96]. Chondrocytes' membranes are composed of cholesterol which is synthesized by them due to their ability to activate cholesterol biosynthesis mechanisms [97,98].