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Gene Expression Via an Autoregulatory Loop Mechanism
Department of Biotechnology (Y.L., C.B., J.W.-D., S.L., S.K.P., C.X., D.S.L.), Mail Zone AA305E, Pharmacia Corp., St. Louis, Missouri 63198; Department of Cardiovascular and Metabolic Disease (G.B.), Pharmacia Corp., Creve Couer, St. Louis, Missouri 63167
Address all correspondence and requests for reprints to: Dr. Deepak Lala, Department of Biochemistry and Molecular Biology, Pharmacia Corp., 700 Chesterfield Parkway North, St. Louis, Missouri 63198.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(hLXR) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2–4 h. Analysis of the hLXR promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXR:RXR and LXRß:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXR:RXR (type II LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXR and LXRß activity, whereas the type II LXRE acts as a weaker and selective mediator of LXR activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXR gene expression. This would lead to increased hLXR levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(1, 2). LXRs and FXR act as sensors for oxysterols and bile acids respectively, whereas PPARs can act as sensors for fatty acids, prostaglandins, and oxidized LDL (oxLDL) in various cell types (2). Thus, collectively, PPARs:RXR, LXRs:RXR, and FXR:RXR appear to form the basis for a regulatory network, involved in the control of lipid homeostasis in metabolically active cells, which mediates the response to autocrine and paracrine signaling molecules. Recent work from many laboratories has begun to define pathways for cholesterol efflux from lipid-laden macrophages. Two members of the ATP binding cassette (ABC) family of transporters, ABCA1 and ABCG1, have been shown to be highly induced in macrophages loaded with lipids, and ABCA1 appears to play a pivotal role in cellular cholesterol efflux (3, 4, 5, 6, 7). Recent evidence suggests convergence of LXR and PPAR signaling pathways on cholesterol efflux and the LXR gene has been shown to be a direct target for PPARs (8, 9). Macrophages respond to oxLDL by increased expression of both PPAR
and LXR that also provides a source of ligands for both receptors (8, 9). This unanticipated link between two nuclear receptors suggests a transcriptional cascade that is activated in response to PPAR and LXR ligands to coordinately regulate the macrophage response to lipid loading. In this report, we provide evidence for another unexpected link, one of direct autoinduction of LXR gene expression in response to LXR ligands. Using a recently identified synthetic LXR ligand T0901317 (3, 10), we demonstrate that LXR gene expression is up-regulated in a dose- and time-dependent fashion in differentiated human THP-1 cells. This induction is direct and mediated via LXR response elements (LXREs) present within the hLXR promoter. This autoregulation also occurs in other cells such as human skin fibroblasts, indicating this effect is not restricted to differentiated macrophages. Our data indicates the presence of a previously unanticipated autoregulatory loop for LXR that is triggered upon exposure of cells to LXR ligands leading to robust induction of the LXR-ABCA1 pathway in a precise and reversible manner. |
RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Gene Expression in Response to LXR Ligands within Differentiated Macrophages levels appear to be fairly low in many cell types including peritoneal macrophages (Ref. 7 and data not shown). Addition of LXR to various cell types leads to further induction of ABCA1 and cholesterol efflux, indicating increased LXR levels can lead to further induction of the ABCA1 pathway (5, 11). Also, LXR gene expression was recently shown to be induced by PPAR ligands (8, 9), indicating that it is an inducible gene. We therefore hypothesized, to get a robust induction of the LXR-ABCA1 system by LXR, LXR gene expression may also be up-regulated by its ligands. To test this, we examined the influence of the synthetic LXR agonist T0901317, a potent LXR ligand with EC50 values of approximately 50 nM on LXR and LXRß (10), on LXR gene expression in human differentiated THP-1 cells and primary mouse peritoneal macrophages. THP-1 cells were treated with 20 ng/ml PMA for 24 h for attachment and exposed to T0901317 (500 nM) overnight. Peritoneal macrophages, isolated from mice injected ip with thioglycolate solution, were allowed to adhere for at least 6 h, then treated with the LXR ligand overnight. LXR mRNA was measured using a highly quantitative real-time PCR method. T0901317 treatment led to a significant increase of LXR gene expression in the human THP-1 cells but, surprisingly, not in primary mouse macrophages (Fig. 1A
). LXR induction was also not observed within the intestinal mucosa in vivo after overnight treatment of mice with the LXR ligand T0901317 although ABCA1 was clearly induced (Fig. 1B). The natural LXR ligand 22(R) hydroxycholesterol (22R) is also incapable of inducing mLXR gene expression in RAW 264.7 cells, a mouse macrophage cell line, although it induced ABCA1 (Fig. 1C). On the other hand, 22R is fully capable of inducing hLXR in human THP-1 cells, consistent with its induction by the synthetic LXR ligand. Interestingly, hLXRß was not induced (Fig. 2A). We therefore proceeded to study LXR gene induction in more detail in the human THP-1 cells. Next, we looked at the induction of LXR in response to increasing amounts of the LXR ligand. As shown (Fig. 2B), LXR gene induction was induced in a dose-dependent manner in response to T0901317, with an EC50 comparable to that observed in transient transfection studies with LXR and ß. Again, although THP-1 cells appear to express comparable levels of LXR and LXRß, no induction of LXRß was observed in response to T0901317 (Fig. 2B). This is similar to the effects of PPAR ligands that only appear to induce LXR but not LXRß gene expression (9). Thus, in THP-1 cells, exposure to LXR ligands leads to a significant and selective increase in LXR gene expression.
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gene expression goes up beginning at 2 h (2-fold) and appears to rise up to 12 h, and these levels are maintained till at least 24 h (Fig. 2C
). Again, no induction of LXRß was observed at these time points (Fig. 2C). In the same experiment, we also determined the time-course of ABCA1 response to T0901317. Coincident with the induction of LXR gene expression, ABCA1 expression also goes up at about 2 h and is maintained till about 24 h (Fig. 2D). The RXR-specific ligand (rexinoid) LG268 (12) that would be expected to induce both ABCA1 and LXR gene expression via LXR:RXR and PPAR:RXR, also exhibited a similar time-dependent response (data not shown).
Induction of LXR in Human Skin Fibroblasts
Human skin fibroblasts have also been shown to induce the LXR-ABCA1 pathway in response to LXR ligands (5). We therefore looked to see if LXR could be induced in these cells. As shown in Fig. 3A, treatment of human skin fibroblasts with T0901317 or the rexinoid LG268 leads to an induction of LXR gene expression. Coadministration of the two compounds has an additive effect. As observed in THP-1 cells, LXRß mRNA was not induced by either T0901317 or LG268 (Fig. 3B). ABCA1 responded in a similar fashion, although its fold activation was higher than LXR induction (Fig. 3C). Treatment of HepG2 cells with the LXR ligand also led to an up-regulation of LXR gene expression (data not shown). These results indicate that hLXR autoinduction occurs in other human cell-types besides macrophages and is specific for the isoform.
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Promoter promoter may be a direct target for LXR:RXR heterodimers via binding to LXR response elements (LXREs) present within its promoter. LXREs are comprised of DNA sequences containing two direct repeats of the hexanucleotide motif AGGTCA spaced by four nucleotides, referred to as a DR-4 element. To look for LXREs, we scanned 5 kb of the hLXR promoter sequence contained in the published human genomic clone (AC018410) by a regular expression search using the FINDPATTERNS algorithm from the Genetic Computing Group (GCG) Wisconsin package (see Materials and Methods). Using this approach, we found three putative LXREs at nucleotides -4139/-4115, -3290/-3266, and -2918/2894 within the 5' region of the hLXR promoter. The LXREs at -3290/-3266, and -2918/2894 are identical, whereas the one at -4139/-4115 is unique (Fig. 3A). Next, we tested the ability of these LXREs to bind to LXR:RXR heterodimers using EMSA. As shown (Fig. 4A), the LXRE at -4139/-4115 bound with strong affinity to both LXR and ß, the other LXRE bound preferentially to LXR but with weaker affinity. An interesting feature of the LXREs at -3290/-3266, and -2918/2894 is that they are present within highly repetitive Alu sequences, which are also conserved within the hLXR promoter (data not shown). These differences suggest the existence of at least two unique classes of LXREs. To distinguish between the two, we designate the LXRE at -4139/-4115 as type I LXRE; this binds to both LXR and ß, and the other two as type II LXREs. None of these LXREs were conserved within the mouse LXR promoter (data not shown), consistent with the lack of induction of mLXR gene expression by LXR ligands.
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, B and C), in these experiments, the two types of LXREs respond in different ways to both ligand and LXR isoforms. Type I LXRE is induced by T0901317 without adding exogenous LXR, indicating cellular receptor levels are sufficient for binding and activating this response element, consistent with the ability of both LXR and ß to bind to this sequence with high affinity. Addition of either LXR or ß to the cell leads to high induction of reporter activity even in the absence of ligand, addition of ligand leads to a further increase, albeit a small one. This is most likely due to the high basal induction observed upon addition of the receptors alone, thereby leading to a saturation of the response. In contrast, the type II LXRE is entirely dependent upon the addition of receptors and ligand for activation, and, also depends on the LXR isoform added. While LXR leads to a dramatic increase in reporter activity in the presence of ligand, addition of LXRß has little effect. This is consistent with the EMSA results, which indicated that the type II LXRE has a higher affinity for LXR than LXRß. These experiments suggest that, while both type I and type II sequences function as bona fide LXREs in the context of heterologous promoters, they do so in different ways. Type I acts as a high affinity LXRE that binds both LXR and ß, whereas the type II sequence functions as a low affinity LXR-selective response element.
Deletion and Mutational Analysis of the hLXR Promoter
To further analyze the roles of the LXREs, nucleotides -4924/+35 of the hLXR promoter (AC018410) was cloned upstream of pGL3, a luciferase reporter construct (wild-type, Fig. 4A). We also created a series of deletions, which deleted either the type I LXRE (deletion I), the two type II LXREs (deletion II), or both types I and II LXREs (deletions I and II) (Fig. 5A). Next, we compared the ability of these promoter-reporter constructs to respond to T0901317 in transient transfection assays in Huh-7 cells. As shown in Fig. 5B, the wild-type promoter is induced by the LXR ligand and deletion of type I LXRE leads to a dramatic loss in induction. Surprisingly, deletion of both type II LXREs has no effect under these conditions, whereas deletion of all three LXREs completely abolishes the induction. Addition of LXR or LXRß did not lead to further induction of constructs with intact type II sequences, if type I was deleted, similar results were obtained in HepG2 cells (data not shown). To further test the contribution of the various LXREs in hLXR promoter activation by LXR ligands, we created point mutations within the type I and II LXREs (Fig. 5C). The type I mutant is a two-base change within the LXRE at -4139/4115, the type II mutant 1 is a two-base mutation within the type II LXRE at -2918/-2894, whereas the type II mutant 2 is a two-base mutation in both type II LXREs. Consistent with the deletions, mutation of the type I LXRE leads to a dramatic loss in the ability of the promoter to respond to T0901317. Mutations within the type II LXREs do not affect the ability of the promoter to respond to LXR ligands. These data indicate that the type I LXRE plays a critical role in hLXR gene induction, whereas the type II LXREs do not, at least under these experimental conditions.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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/ß responds to sterols and governs the uptake of dietary cholesterol in enterocytes as well as cholesterol efflux in macrophages via regulation of the ATP transporter ABCA1. FXR is activated by bile acids and triggers a cascade in the liver to coordinate the degradation of cholesterol and bile acid secretion (13, 14, 15). PXR/SXR, in response to select bile acids also coordinately regulates genes involved in the biosynthesis, transport, and metabolism of certain bile acids (16). RXR participates in these pathways as a heterodimer partner for LXRs, FXR, and PXR/SXR. Recently, another RXR heterodimer, PPAR:RXR, which is activated by several compounds including fatty acids, oxLDL, and prostaglandins, and is known for its role in lipid and glucose metabolism, was also implicated in the regulation of cholesterol efflux. PPAR is expressed in macrophages and activates LXR gene expression in response to PPAR ligands (9). PPAR may also play similar a role (8). Thus, there is considerable cross-talk between nuclear receptors, which is likely to be important in regulating pathways of cholesterol and lipid homeostasis.
Here, we show an additional mode of regulation with respect to cholesterol efflux, that of autoinduction of LXR in response to its ligands. Using a synthetic LXR ligand as a chemical tool, we demonstrate that hLXR gene expression is autoinducible. We have identified three LXREs within the hLXR promoter, one of which (LXRE type I) functions as a high affinity binding site for both LXR:RXR and LXRß:RXR and plays a critical role in mediating this response.
We also identified two additional and unique LXREs (LXRE type II), these exist within Alu repeats, which are themselves conserved within the hLXR promoter. Interestingly, these elements act as low affinity binding sites that are selective for LXR:RXR heterodimers and do not bind well to LXRß:RXR. These sequences appear to play a minimal role in hLXR gene induction by LXR, under the conditions used. Although these results suggest that the type II LXREs are not important in hLXR induction by LXR ligands, the presence of these sequences is particularly intriguing. Functional HREs for the estrogen and RARs have been previously identified within Alu repeats (17, 18, 19), suggesting these sequences should be considered as important regulatory elements. The type II LXREs are also capable of selective binding and activation by LXR, at least when present within heterologous promoters. The apparent preference of the type II LXREs for LXR suggests a possible role for these elements to accommodate the selective increase of LXR levels within the cell.
It is interesting to note that hLXRß does not seem to be induced by LXR ligands. While there are several known similarities between LXR and ß, there are also several differences. Both isoforms share fairly well conserved ligand binding domains (78% amino acid homology) and both respond to endogenous oxysterol ligands. LXR and ß are both thought to be involved in the regulation of cholesterol metabolism in peripheral tissues via regulation of ABCA1 and ABCG1 (6, 7). However, their expression patterns are different, LXR is expressed selectively in lipid metabolizing tissues such as kidney, adipose tissue, liver, intestine, and adrenals, LXRß is expressed ubiquitously. While the role for LXR as a key regulator of hepatic cholesterol metabolism is supported by the inability of LXR -/- mice to regulate catabolism of dietary cholesterol in the liver, LXRß does not appear to have a comparable role (20). Here we highlight another key difference between the two isoforms: hLXR is autoinducible, whereas hLXRß is not.
While LXR gene expression is up-regulated in multiple human cell lines, we failed to see LXR autoinduction in vivo or in cultured mouse cells (Fig. 1A and data not shown). Although both mouse and human LXR promoters are induced by PPAR ligands (9), only the endogenous human LXR gene is induced in response to LXR ligands. Other aspects of LXR gene regulation also appear to be species dependent. The role of LXR in induction of rodent CYP7a, the rate limiting step in cholesterol conversion to bile acids in the liver, has clearly been established (21). However, there is no evidence that LXR is an activator of human CYP7a. In fact, recent studies suggest LXR has little or no effect on the hamster and human CYP7a promoter (22). Cholesterol metabolism in rats and mice is very different from humans and other species (22). Our data suggests that LXR signaling pathways also vary between rodents and humans.
Finally, it is interesting to note that other RXR heterodimer partners are also autoregulated. A good example is the RAR, which acts as a sensor for RA levels (23). The morphogenetic roles of RA in limb bud regeneration and in neural identity specification are well known. Here, RAR responds to levels of RA and initiates a positive feedback loop by activating RAR gene expression via a RAR response element (DR-5) (24). For morphogenesis, this model provides an exquisitely precise mechanism to respond to RA gradients. The positive feedback loop by LXR may represent a similar response to LXR ligands such as oxysterols. This system would also be expected to be reversible; in the basal state, there may be some LXR:RXR- and LXRß:RXR-mediated transcription. Upon ligand stimulation, LXR levels would increase and shift the balance in favor of LXR:RXR, leading to an amplification of the response. When ligand concentrations decrease, the cell returns to its basal state of gene transcription. Through induction of LXR levels in response to cholesterol-derived ligands, the LXR-ABCA1 pathway would facilitate the elimination of excess cholesterol in macrophages and other cell-types; additionally, cholesterol buildup, through inhibition of sterol regulatory element-binding protein proteolytic cleavage, would prevent de novo cholesterol synthesis or uptake of additional cholesterol (25). This would allow cells to exert a tight control of both intra- and extracellular levels of cholesterol.
In conclusion, we have discovered a novel autoregulatory loop for LXR, which occurs in multiple human cell types including macrophages. This provides a unique sensory mechanism used by cells to respond to increasing cholesterol levels, by generating LXR ligands, leading not only to activation of the receptor, but also to increased receptor levels within the cell, potentially leading to an amplification of the response to oxysterols and of the LXR-ABCA1-cholesterol efflux pathway.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Quantitative Real-Time PCR
Quantitative PCR analysis was conducted on the ABI Prism 7700 and 7900 Sequence Detectors. Primer-probe sets were designed using Primer Express 1.5 (ABI, Foster City, CA) and evaluated for their efficiency and linear range using standard curves. RT-PCR reactions were performed using the ABI One-Step-RT-PCR Kit. Relative expression was determined using the comparative CT method. Multiple primer probe sets designed against different regions of LXR gave similar results.
Identification of LXREs
The REFSEQ sequence for human LXR mRNA (NM_005693) was used to find the genomic clone containing the LXR gene by BLAST against the human high-throughput genomic sequences. The sequence matching the first exon and 5000 nucleotides upstream was selected from the genomic clone AC018410. To look for LXREs, we scanned this region by a regular expression search using the FINDPATTERNS algorithm [Genetic Computing Group (GCG)]. In silico analyses for promoter regulatory elements were performed by MATINSPECTOR (26).
Plasmid Constructs
Human LXR promoter (AC018410) containing nucleotides -4924 to +35 (based on +1 as transcription start site of NM_005693) was PCR amplified from human genomic DNA (CLONTECH Laboratories, Inc.) and cloned into the pGL3-Basic vector (Promega Corp., Madison, WI). All deletions were generated from the wild-type construct using existing restriction sites. All mutants were generated using the QuickChange Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA). For the type I/type II LXRE reporter constructs, 3x double-stranded oligos (for type I, -4139 to -4115, for type II, -3290 to -3266) were cloned to KpnI-XhoI site of pTAL-Luc vector (CLONTECH Laboratories, Inc.). All plasmid constructs were verified by sequencing.
Gel Mobility Shift Assays
Human LXR, LXRß, and RXR were synthesized in vitro using the TNT quick-coupled transcription/translation system (Promega Corp.). Double-stranded oligonucleotides used in EMSA were prepared by annealing both strands of each LXR response element in human ABCA1 (5'-gatcGGCTTTGACCGATAGTAACCTCTGCG-3') and human LXR promoter (5'-gatcACTCCTGACCTCAAGTGATCCATCTG-3'), labeled using Klenow. Labeled probes were incubated with receptors in 10 mM Tris (pH 7.5), 50 mM NaCl, 0.5 mM EDTA, 4% glycerol, 1 mM DTT, 0.1 mg/ml poly(deoxyinosine-deoxycytidine), and 0.03% NP-40 for 30 min at room temperature. DNA-protein complexes were resolved on a 6% polyacrylamide gel.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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gene expression within human macrophages came into the public domain.
Abbreviations: ABC, ATP binding cassette; EC50, concentration of ligand that produces 50% of maximal effect; FXR, farnesoid X receptor; HRE, hormone response element; hLXR or ß, human LXR or ß; LXR, liver X receptor; LXRE, LXR response element; oxLDL, oxidized LDL; RPMI, Roswell Park Memorial Institute.
Received for publication September 10, 2001. Accepted for publication November 14, 2001.
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as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol 20:4436–4444. Proc Natl Acad Sci USA 97:12097–102 and PPAR- activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 7:53–58[CrossRef][Medline]
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