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Endocrinology Vol. 141, No. 11 4180-4184
Copyright © 2000 by The Endocrine Society

ARTICLES

Cholestenoic Acid Is a Naturally Occurring Ligand for Liver X Receptor {alpha}1

Ching Song and Shutsung Liao

Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Dr. Shutsung Liao, Ben May Institute for Cancer Research, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: sliao{at}ben-may.bsd.uchicago.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Excessive cholesterol is eliminated from extrahepatic cells by reverse cholesterol transport, a process by which neutral sterols are transferred to extracellular acceptor lipoproteins for further transport to the liver. Another process independent of lipoproteins involves excretion of 3ß-hydroxy-5-cholesten-25(R)-26-carboxylic (cholestenoic) acid, a metabolite of 27-hydroxycholesterol. Physiological concentrations of cholestenoic acid activated the nuclear receptor liver X receptor {alpha} (LXR{alpha}; NR1H3), but not other oxysterol receptors. As a ligand, cholestenoic acid modulated interaction of LXR{alpha} with the nuclear receptor coactivator Grip-1. Cholestenoic acid, therefore, may function as a signaling molecule for regulation of lipid metabolism via LXR{alpha}.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
STEROL 27-HYDROXYLASE IS a mitochondrial P450 enzyme that catalyzes multiple oxidation at the C-27 position of the sterol side-chain, of substrates such as cholesterol and 5ß-cholestane-3{alpha},7{alpha},12{alpha}-triol (1). 27-Hydroxylase catalyzes a step in liver bile acid formation, but it is also expressed in extrahepatic tissues, indicating an additional role beyond bile acid synthesis (2). Mutations in the sterol 27-hydroxylase gene (CYP27) cause cerebrotendinous xanthomatosis (CTX) (3, 4, 5), an autosomal recessive cholesterol metabolic disorder characterized by excessive sterol deposition in peripheral tissues, which causes neurological abnormalities, accelerated atherosclerosis, osteoporosis, and cataracts. In the liver of CTX patients, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity and total cholesterol synthesis are elevated (6). Although the rate of total bile acid synthesis is subnormal in CTX patients, cholic acid is synthesized by a compensatory pathway involving 25-hydroxylated bile alcohols; therefore, there is no obvious problem in lipid absorption in CTX patients. Serum cholesterol is maintained at a normal level, but the level of high density lipoprotein is subnormal (6). Although the mechanism by which sterol 27-hydroxylase deficiency produces CTX remains speculative, an impairment in reverse cholesterol transport via 27-hydroxycholesterol and cholestenoic acid in macrophages has been suggested to be the primary cause for xanthomas and premature atherosclerosis (2).

Mice with a null CYP27 gene share a similar, but distinct, phenotype with CTX patients (7). These mutant mice maintain a normal serum cholesterol level and elevated levels of HMG-CoA reductase and cholesterol 7{alpha}-hydroxylase in the liver. Bile acid production is suppressed, but no CTX-related pathological abnormalities are observed. In these mutant mice, sterol 27-hydroxylase deficiency becomes life-threatening when mice are fed an atherogenic diet, indicating that sterol 27-hydroxylase is important for cholesterol catabolism in mice (7).

It is evident that sterol 27-hydroxylase is the sole enzyme in both humans and mice responsible for production of serum 27-hydroxycholesterol and possibly cholestenoic acid. Both CTX patients (8) and mice (7) with a defective CYP27 gene have undetectable serum levels of 27-hydroxycholesterol (<2.5 nM), whereas the normal level is 100–500 nM (9). In addition, heterozygous mice have half the normal level of 27-hydroxycholesterol, suggesting that both alleles are needed to maintain normal levels. Although 27-hydroxycholesterol and other neutral oxysterols are mostly esterified to fatty acids and bound to lipoproteins in serum (10), cholestenoic acid exists unesterified and unconjugated with a blood concentration of approximately 300–500 nM in humans (9). Cholestenoic acid is most likely absent in CTX patients and mice with CYP27 null genes due to the lack of its metabolic precursor 27-hydroxycholesterol.

Serum levels of 27-hydroxycholesterol and cholestenoic acid are also controlled by at least one other P450 enzyme, oxysterol 7{alpha}-hydroxylase, which catalyzes 7-hydroxylation of both sterols (9). Oxysterol 7{alpha}-hydroxylase encoded by the CYP7B gene is expressed in liver and extrahepatic tissues. An individual with oxysterol 7{alpha}-hydroxylase deficiency due to mutant CYP7B genes had serum concentrations of 781 µM for 27-hydroxycholesterol and 24 µM for cholestenoic acid (9).

Unlike neutral sterols, which require extracellular lipoproteins for excretion from extrahepatic cells, cholestenoic acid only requires albumin as an acceptor for cellular export. We hypothesized that cholestenoic acid might be acting as a signaling molecule, e.g. a sensor of the intracellular cholesterol level involved in the control of cholesterol metabolism. We tested its ability to modulate two oxysterol nuclear receptors, RLD-1/liver X receptor (LXR{alpha}; NR1H3) (11, 12) and UR/NER/RIP15/OR-1 (UR; NR1H2) (13, 14, 15, 16), both of which were cloned by homology screening and later demonstrated to be activated by a subset of oxysterols with a hydroxylated side-chain (17, 18, 19, 20).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Trans-activation assay
Human embryonic kidney 293 cells were seeded into 48-well culture plates at 2 x 104 cells/well in DMEM supplemented with 10% FBS. After 24 h, cells were transfected by a calcium phosphate coprecipitation method with 250 ng of a pGL3/UREluc reporter gene, which consists of three copies of AGGTCAagccAGGTCA fused to nucleotides -56 to +109 of the human c-fos promoter in front of the firefly luciferase gene in the plasmid basic pGL3 (Promega Corp., Madison, WI), 40 ng pSG5/human retinoid X receptor {alpha} (hRXR{alpha}), 40 ng pSG5/rUR (13) or CMX/hLXR{alpha} (12), 10 ng pSG5/hGrip1 (21), 0.4 ng thymidine kinase/R-luc (transfection normalization reporter, Promega Corp.), and 250 ng carrier DNA/well. Alternatively, 500 ng of the pGL2/7aluc reporter gene (22), which consists of a single copy of nucleotides -101 to -49 of the rat 7{alpha}-hydroxylase gene fused to the simian virus 40 promoter in front of the firefly luciferase gene in the plasmid basic pGL2 (Promega Corp.), were used instead of pGL3/UREluc. In some experiments, 500 ng of the human 7{alpha}-hydroxylase gene reporter PH/hCYP7A-135 (23), which consists of a single copy of nucleotides -135 to +24 of the human CYP7A gene fused to the firefly luciferase gene in the plasmid basic pGL3 (Promega Corp.), were used instead of pGL2/7aluc. After another 12–24 h, cells were washed with PBS and refed DMEM supplemented with 4% delipidated FBS. Chemicals dissolved in ethanol were added in duplicate or triplicate (data shown are the mean ± SEM) to the medium, so that the final concentration of alcohol was 0.2%. After 24–48 h, cells were washed and lysed, and luciferase activity was measured with a commercial kit (Promega Corp., Dual Luciferase II) on a Monolight luminometer (Becton Dickinson and Co., Mountain View, CA). Coexpression of the human ileal bile acid transporter from an expression vector HIBT in 293 cells did not further improve the trans-activation of the pGL3/UREluc reporter gene by conjugated steroids (data not shown). All transfection experiments were repeated at least twice to demonstrate reproducibility. Steroids were purchased from Steraloids (La Jolla, CA) or Sigma (St. Louis, MO) or were synthesized using published methods. The purity of the synthesized compounds, verified by TLC, proton and 13C magnetic resonance spectrometry, and/or high resolution fast atom bombardment mass spectrometry, was no less than 95%.

Coactivator-receptor-ligand binding assay
A glutathione-S-transferase (GST)-LXR{alpha} fusion protein was expressed in Escherichia coli strain BL21 using the expression plasmid pGEX. Cells were lysed by one cycle of freeze-thaw and sonication. The agarose was washed with binding buffer [1% fat-free milk powder, 20 mM HEPES (pH 7.5), 5 mM ß-mercaptoethanol, 1 mM dithiothreitol, 0.5 mM phenylmethylsulfonylfluoride, and 2 µg/ml aprotinin]. Human Grip1 was produced by in vitro translation using a rabbit reticulocyte lysate and labeled with [35S]methionine. [35S]Grip1 in reticulocyte lysate (5 µl) was added to GST-LXR{alpha} bound to agarose beads in 100 mM binding buffer. Test chemicals in DMSO were added to the mixture, and the slurry was shaken at 4 C for 30 min. The agarose beads were then washed three times with binding buffer. Bound protein was eluted with SDS-PAGE loading buffer and separated on an 8% SDS-PAGE gel. Gels were dried and subjected to autoradiography. Radioactive Grip1 was measured with a STORM PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA). Alternatively, radioactive eluent was quantified using a scintillation counter.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
As shown in Fig. 1AGo, a dose-response analysis of the activation of a LXR{alpha}/UR reporter gene using a cell-based transfection assay revealed that cholestenoic acid activated LXRA with a half-maximum effective dose (ED50) of 200 nM, which is near the physiological concentration in human plasma. The closely related receptor, UR, was also activated by cholestenoic acid with an ED50 greater than 5 µM, several times higher than the physiological concentration. In agreement with previous studies (18), the cholestenoic acid precursor 27-hydroxycholesterol activated LXR{alpha} and UR with ED50 in micromolar concentrations (Fig. 2Go). Some potential liver metabolites of cholestenoic acid and their ED50 values for reporter gene activation are shown in Fig. 2Go. Metabolite C was less potent than cholestenoic acid for activation of LXR{alpha} or UR. Because the individual with an oxysterol 7{alpha}-hydroxylase deficiency had an abnormally high level of 3ß-hydroxy-5-cholenoic acid (87 µM), we tested the activity of this steroid and its conjugated forms, taurocholenoic acid and taurocholenoic acid 3-sulfate. Only taurocholenoic acid trans-activated LXR{alpha} and UR. Other {Delta}5-steroid carboxylic acids with shorter side-chains, androgenic acid and 22,23-nor-cholenoic acid, were also inactive (data not shown). Another {Delta}5-steroid carboxylic acid with an additional double bond and a different configuration at the 17 position (J) was less potent than cholestenoic acid on both LXR{alpha} and UR. A known ligand for LXR{alpha} and UR, N,N-dimethyl-3ß-hydroxy-5-cholenamide (compound K, Fig. 2Go) (20), activated both LXR{alpha} and UR with an ED50 of approximately 100 nM (Fig. 1CGo). A related compound L (Fig. 2Go), however, preferentially activated LXR{alpha} over UR (Fig. 1BGo). In addition, another nuclear receptor, steroidogenic factor-1, which is also regulated by oxysterols (24), failed to trans-activate one of its target genes in the presence of cholestenoic acid (25). These structure-activity relationships clearly established that cholestenoic acid is an important naturally occurring selective activator for LXR{alpha} with physiological significance.



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  		Figure 1. Trans-activation of a luciferase reporter gene by selective activation of LXR{alpha} or UR by cholestenoic acid (A), compound L (B; see Fig. 2Go), and compound K (C; see Fig. 2Go), a known LXR{alpha} and UR ligand (20 ). Cells were treated with increasing concentrations of compounds after transfection with the pGL3/UREluc reporter and LXR{alpha} (•) or UR ({circ}) expression plasmids and were assayed for luciferase activity after lysis. RLU, Relative light unit.

 


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  		Figure 2. Trans-activation of a luciferase reporter gene by activation of LXR{alpha} by cholestenoic acid and related compounds. The half-maximum effective doses (ED50) of the compounds needed to trans-activate the pGL3/UREluc reporter gene in the presence of LXR{alpha} are listed. ND, Not determined.

 
As the affinity of nuclear receptors for coactivators increases in an agonist-dependent manner to augment transcription, binding of radioactive coactivators to nuclear receptors can be used to measure ligand-receptor interactions without using radioactive ligands. We used this assay to study in vitro interaction of cholestenoic acid and LXR{alpha}. We found that with increasing concentrations of cholestenoic acid, more 35S-labeled nuclear receptor coactivator Grip1 was complexed with LXR{alpha}. In a dose-response analysis, cholestenoic acid increased the amount of [35S]Grip1 bound to LXR{alpha}, with a half-maximal effective concentration (EC50) of 300 nM, which correlates with the cell-based transfection assay (Fig. 3Go). These data are consistent with cholestenoic acid being a LXR{alpha} agonist that binds to LXR{alpha} without metabolic conversion and, therefore, should be considered an endogenous ligand for LXR{alpha}.



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  		Figure 3. Evidence for the direct interaction of cholestenoic acid with LXR{alpha}. Coactivator-receptor-ligand assay was performed using bacterially expressed GST-LXR{alpha} and [35S]Grip1 synthesized in vitro. [35S]Grip1 was mixed with GST-LXR{alpha} in the presence of increasing concentrations of cholestenoic acid ({circ}) or a known LXR{alpha} ligand N,N-dimethyl-3ß-hydroxy-5-cholenamide (•) (20 ). [35S]Grip1 complexed with GST-LXR{alpha} bound to glutathione-agarose beads was eluted. The amount of radioactivity was quantified with a scintillation counter.

 
The function of LXR{alpha} has been studied by characterizing mutant mice with null LXR{alpha} genes (26). Mice with a LXR{alpha} deficiency when fed a high cholesterol diet failed to increase the production of bile acids and accumulate cholesteryl esters in the liver. Expression of HMG-CoA reductase was up-regulated, and enzymes for fatty acid synthesis were down-regulated due to lack of LXR{alpha}. Genes that code for cholesterol 7{alpha}-hydroxylase (18) and cholesteryl ester transfer protein (CETP) (27) have been identified as target genes of LXR{alpha}, since cis-acting elements bound by LXR{alpha}/RXR heterodimer are found in their promoters. Transcription from the reporter genes constructed using these cis-elements was also up-regulated by LXR{alpha} in the presence of LXR{alpha} ligands. The importance of CETP in reverse cholesterol transport has been elucidated by human genetic deficiency of CETP, which is associated with excess of coronary heart disease even when high density lipoprotein levels are high (28). We tested the ability of cholestenoic acid to trans-activate reporter genes containing natural promoters of the rat and human cholesterol 7{alpha}-hydroxylase gene. As shown in Fig. 4Go, in the presence of LXR{alpha}, cholestenoic acid promoted the expression of both reporter genes in a dose-dependent manner, indicating that cholestenoic acid can modulate expression of the rate-limiting enzyme of bile acid synthesis in the liver. In a previous report (29), the putative degenerate LXRE (-74 to -54) in human CYP7A promoter failed to interact with LXR{alpha} in vitro using a gel shift assay. The human CYP7A promoter reporter used here covers a longer region. The use of cell line 293 and cotransfection of expression vector for a co-trans-activator Grip 1, which all may contribute to the differences observed in human CYP7A promoter activity between the data presented here and previously published results. Whether the modulation of CYP7A promoter activity by LXR{alpha} is direct or indirect remains to be determined.



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  		Figure 4. Trans-activation of LXR{alpha} using the reporter gene pGL2/7aluc containing the rat cholesterol 7{alpha}-hydroxylase (-101 to -49)/simian virus 40 promoter or PH/hCYP7A-135 containing the human cholesterol 7{alpha}-hydroxylase promoter (-135 to +24; •) by cholestenoic acid or by a known LXR{alpha} ligand, N,N-dimethyl-3ß-hydroxy-5-cholenamide ({blacksquare}) (20 ). Open symbols represent control transfection without the LXR{alpha} expression plasmid. Ligands were added to transfected cells at increasing concentrations. After 24 h of treatment, luciferase activity expressed from the reporter genes was measured.

 
Among the identified ligands of LXR{alpha}, 24S,25-epoxycholesterol has been suggested to be another physiologically relevant ligand (18, 20). The endogenous epoxycholesterol in human liver was reported to be around 10–30 µM (30). However, in this measurement experiment, extracted lipids underwent saponification before HPLC separation; therefore, both free and esterified epoxycholesterol were included for measurement. Whether esterified epoxycholesterol binds LXR{alpha} remains unknown. This naturally occurring sterol is also a potent inhibitor of HMG-CoA reductase in cell culture (31, 32), with an IC50 of 0.89 µM in L cells (33). In one report, mice fed a 3% cholesterol diet did not accumulate epoxycholesterol at concentrations high enough in liver to inhibit HMG-CoA reductase activity (34). In addition, in whole animal studies the administered epoxycholesterol was found to undergo rapid inactivation and degradation in the liver (35). The cellular concentration of free epoxycholesterol in the liver and extrahepatic tissues remains to be determined.

The discovery of a cholestenoic acid signaling pathway mediated by LXR{alpha} complements the extensive pioneering studies that have defined the acidic (alternative) bile acid synthesis pathway and lipoprotein-independent reverse cholesterol transport. The pharmacological utility of cho-lestenoic acid and other LXR{alpha} agonists for patients with CTX or other pathological conditions, including atherosclerosis, shall be explored.


   Acknowledgments
 
The authors thank Dr. J. Y. Chiang for the rat pGL2/7aluc and human PH/hCYP7A-135 7{alpha}-hydroxylase reporter plasmids, Dr. D. J. Mangelsdorf for CMV/hLXRa, Dr. M. Stallcup for pSG5/hGrip1, Dr. Q. Dai for chemical synthesis of compounds B and J, and Dr. R. A. Hiipakka for technical assistance.


   Footnotes
 
1 This work was supported by NIH grants. Back

Received June 2, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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