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Nuclear Receptor Discovery Research (B.G., M.A.W.), GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709; Department of Molecular & Integrative Physiology (H.K., J.M., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and Department of Molecular Biology (S.A.K.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8594
Address all correspondence and requests for reprints to: Bryan Goodwin, Nuclear Receptor Discovery Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, E-mail: bryan.j.goodwin{at}gsk.com, and/or Steven A. Kliewer, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8594. E-mail: steven.kliewer{at}utsouthwestern.edu.
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ABSTRACT |
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-hydroxylase (CYP7A1), which catalyzes the rate-limiting step in the classic bile acid synthetic pathway, is stimulated by the liver X receptor (LXR), a nuclear receptor for oxysterol metabolites of cholesterol. This feed-forward regulatory loop provides a mechanism for the elimination of excess cholesterol from the body. In this report, we demonstrate that in primary cultures of human hepatocytes, activation of LXR has the opposite effect, repressing CYP7A1 expression. This repression is mediated, at least in part, through induction of the orphan nuclear receptor, short heterodimer partner (SHP), which is also induced by bile acids. We demonstrate that SHP is regulated directly by LXR through a DNA response element that overlaps with the previously characterized bile acid response element. Our data reveal a fundamental difference in the regulation of CYP7A1 in rodent and human hepatocytes and provide evidence that different species employ distinct molecular strategies to regulate cholesterol homeostasis. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The conversion of cholesterol to bile acids in the liver represents an important pathway for the elimination of cholesterol from the body. The first and rate-limiting step in the classic pathway for bile acid biosynthesis involves the 7-hydroxylation of cholesterol, a reaction that is catalyzed by cytochrome P450 (CYP) 7A1. Because of the intrinsic toxicity of bile acids, their synthesis must be tightly regulated (5, 6, 7, 8). Bile acids feed back and suppress CYP7A1 transcription through a mechanism mediated in part by the farnesoid X receptor (FXR; NR1H4), a member of the nuclear receptor family of ligand-activated transcription factors (8). Suppression of CYP7A1 by FXR activation is not direct. Rather, the heterodimer formed between FXR and the 9-cis retinoic acid receptor- (RXR; NR2B1) induces the expression of small heterodimer partner (SHP; NR0B2), an atypical orphan nuclear receptor that lacks a DNA binding domain; SHP, in turn, represses the activity of liver receptor homolog 1 (NR5A2), which binds to the proximal CYP7A1 gene promoter (9, 10). In addition to this nuclear receptor-signaling cascade, there is also recent evidence for SHP-independent mechanisms for suppression of CYP7A1 expression (11, 12). Thus, feedback regulation of bile acid synthesis involves multiple signaling pathways.
In mice and rats, the expression of CYP7A1 is induced by high-cholesterol diets. Recent studies have demonstrated that this feed-forward regulation is mediated through the nuclear liver X receptor (LXR: NR1H3), which is activated by oxysterol metabolites of cholesterol (13, 14) and binds as an RXR heterodimer to a response element located in the proximal promoter of the CYP7A1 gene. LXR-null mice fed a high-cholesterol diet accumulate copious amounts of cholesterol in their livers and eventually succumb to liver failure (15). In addition to CYP7A1, LXR regulates a number of genes involved in cholesterol and/or lipid homeostasis including the ATP-binding cassette proteins (ABC) A1, G1, G4, G5, and G8, apolipoprotein E, cholesterol ester transport protein, lipoprotein lipase, fatty acid synthase, and the sterol-regulatory element binding protein 1 (SREBP-1) (16, 17, 18, 19). Thus, LXR provides a mechanism for sensing cholesterol levels and regulating genes involved in cholesterol homeostasis accordingly.
The regulation of CYP7A1 by cholesterol varies across species. Thus, cholesterol induces CYP7A1 expression in mice, rats, dogs, and certain species of nonhuman primates (3, 20, 21, 22, 23), all species that adapt to high-cholesterol diets with little change in plasma cholesterol levels. In contrast, cholesterol has little effect or even suppresses CYP7A1 in other species including rabbit, hamster, and African Green monkey (2, 3, 24). All of these species develop hypercholesterolemia in response to dietary cholesterol. The effects of cholesterol on the regulation of CYP7A1 are not well characterized in man, but dietary cholesterol does not increase bile acid production at least in certain subjects (25, 26, 27). In agreement with these findings, the LXR response element (LXRE) is not conserved in the human (h) CYP7A1 promoter (28), and the hCYP7A1 promoter is not induced by cholesterol feeding in transgenic mice harboring the gene (29). Thus, there appear to be important interspecies differences in the regulation of CYP7A1. In this report, we have directly compared the effects of LXR agonists on CYP7A1 expression in human and rodent hepatocytes.
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RESULTS |
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9-fold) and SREBP-1 (8-fold) mRNA levels (Fig. 1
, A and E, respectively). In contrast, the natural LXR agonist 22(R)-hydroxycholesterol had only very modest effects on CYP7A1 and SREBP-1 expression in the rat hepatocytes (Fig. 1, A and E, respectively). Although the reason for this lack of activity is not clear, 22(R)-hydroxycholesterol may be either metabolized or inefficiently taken up by primary rat hepatocytes. Neither T0901317 nor 22(R)-hydroxycholesterol had any effect on SHP expression in rat hepatocytes (Fig. 1C). As expected, treatment of rat hepatocytes with the FXR agonist GW4064 resulted in a marked induction of SHP (70-fold) (Fig. 1C) and complete suppression of CYP7A1 (Fig. 1A). Thus, the regulation of SREBP-1, SHP, and CYP7A1 by LXR and FXR is recapitulated in primary cultures of rat hepatocytes.
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, B and D). Thus, FXR agonists have identical effects on SHP and CYP7A1 expression in human and rodent hepatocytes. Surprisingly, treatment of human hepatocytes with either the natural LXR agonist 22(R)-hydroxycholesterol or the synthetic agonist T0901317 also resulted in the induction of SHP expression that was paralleled by a repression of CYP7A1 expression (Fig. 1, B and D). In time course experiments, the effects of T0901317 on SHP and CYP7A1 expression were observed as early as 6 h after treatment (data not shown). In control experiments, 22(S)-hydroxycholesterol had virtually no effect on either CYP7A1 or SHP expression in the human liver cells (Fig. 1, B and D, respectively). As expected, expression of the LXR target gene SREBP-1 was highly inducible by both 22(R)-hydroxycholesterol (6-fold) and T0901317 (8-fold) (Fig. 1F). Expression of the bile salt export pump (ABCB11), an FXR target gene (31, 32), was induced by the FXR agonist GW4064 but not the LXR ligand T0901317 (data not shown). Similar effects of LXR agonists on gene expression were seen in three independent experiments performed using hepatocytes derived from different donors (data not shown). Thus, LXR agonists have completely different effects on SHP and CYP7A1 expression in human vs. rodent hepatocytes.
LXR Activates the hSHP Promoter
We next examined whether LXR directly regulates expression of the hSHP gene. Treatment of primary human hepatocytes with cycloheximide failed to block T0901317-dependent induction of hSHP expression (data not shown), indicating that LXR directly regulates this gene. To further examine this issue, a reporter construct containing 571 bp of the hSHP promoter fused to the luciferase gene was cotransfected into human embryonal kidney cells (HEK293) either in the absence or presence of expression plasmids for hLXR and/or hRXR. T0901317 and/or the synthetic RXR agonist LG100268 had little or no effect on reporter activity in the absence of exogenously expressed LXR and RXR (Fig. 2A). Reporter levels increased in response to expression of either receptor in the presence of its cognate ligand (Fig. 2A). Introduction of both LXR and RXR in the absence of their ligands resulted in an approximately 5-fold increase in reporter activity (Fig. 2A), which was stimulated an additional 2- to 4-fold by treatment with the LXR agonist T0901317 or the RXR agonist LG100268 (Fig. 2A). Cotreatment with T0901317 and LG100268 resulted in additive effects on reporter activity (Fig. 2A). Thus, the LXR/RXR heterodimer can directly activate the hSHP promoter.
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/RXR responsive region, we tested a series of deletion mutants in the hSHP promoter. Deletion to -288 did not reduce the responsiveness of the hSHP promoter to the LXR/RXR complex (Fig. 2B, pGL-hSHP-288). However, further deletion to -266 essentially abolished LXR/RXR activity on the promoter (Fig. 2B, pGL-hSHP-266). Within the region extending from -266 to -288, we identified an imperfect DR-4 motif with similarity to previously characterized LXR/RXR binding sites (Fig. 3A). Interestingly, this motif shares a half-site with the previously characterized FXR/RXR binding site (inset, Fig. 2A), which confers regulation by bile acids on the hSHP promoter. Site-directed mutagenesis of the DR-4 motif markedly decreased the response of the hSHP promoter to LXR/RXR (Fig. 2B, pGL-hSHP-413
LXRE). Moreover, a single copy of this response element was sufficient to confer responsiveness to LXR/RXR on the heterologous thymidine kinase (tk) promoter [Fig. 2B, pGL3-(hSHP-LXRE)-tk-Luc]. These data demonstrate that the DR-4 motif functions as an LXRE in cell-based reporter assays.
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/RXR heterodimer binds directly to the DR-4 element in the hSHP promoter. As expected, LXR bound efficiently as a heterodimer with RXR to the LXRE from the rat CYP7A1 promoter (Fig. 3, A and B). The LXR/RXR heterodimer also bound to the hSHP DR-4, albeit with lower affinity compared with the CYP7A1 LXRE (Fig. 3, B and C). These data indicate that LXR directly regulates expression of the hSHP by binding to a response element located in the promoter of the gene.
SHP Represses the hCYP7A1 Promoter
We next examined whether SHP was capable of repressing transcription of the hCYP7A1 gene in a manner analogous to that described for rat CYP7A1 (9, 10). Transfection of HepG2 cells with a SHP expression plasmid resulted in the repression of the endogenous CYP7A1 gene (Fig. 4). These data suggest that induction of SHP contributes to the repression of CYP7A1 observed in primary cultures of human hepatocytes treated with LXR agonists (Fig. 1).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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results in increased catabolism of cholesterol to bile acids (16, 17, 19, 33). The importance of this pathway is highlighted in mice lacking LXR: these animals accumulate copious amounts of cholesterol in their livers in response to a high-cholesterol diet (15). However, little is known about the role of LXR in the regulation of hCYP7A1 gene. In this study, we compared the regulation of the rat and human CYP7A1 genes in primary hepatocytes. It was anticipated that LXR agonists might not induce CYP7A1 expression in human hepatocytes, since the LXR/RXR binding site is not conserved in the human gene promoter (28). Surprisingly, we found that CYP7A1 was effectively suppressed by LXR agonists in human hepatocytes. This repression of CYP7A1 was accompanied by a corresponding increase in the expression of SHP, which is known to be induced by bile acids and to contribute to the feedback repression of CYP7A1 in rodents (9, 10, 11, 12). In contrast, LXR agonists did not induce SHP expression in rats in vivo (data not shown) or in primary rat hepatocytes. These data indicate that there are fundamental differences in the regulation of CYP7A1 and cholesterol homeostasis in rodents and humans. We speculate that the inhibition of CYP7A1 by LXR agonists may be a component of a broader physiological strategy to suppress the absorption of dietary cholesterol in the intestine. The obligate role of bile acids in the absorption of cholesterol from the intestinal lumen has been appreciated for more than 30 yr (34, 35, 36, 37). Decreases in bile acid pool size by either diversion from the intestinal lumen or sequestration with resins, such as cholestyramine, result in an inhibition of cholesterol absorption (25, 35, 38). Indeed, cholestyramine is reported to have utility in the treatment of patients with hypercholesterolemia (39). Additionally, targeted disruption of the murine genes encoding CYP7A1 or CYP27A1, two key enzymes in bile acid production, results in a reduction in the bile acid pool and a concomitant decrease in the solubilization and absorption of intestinal cholesterol (40, 41, 42). Thus, the repression of CYP7A1 and bile acid synthesis by dietary cholesterol in human hepatocytes may contribute to an overall reduction in cholesterol load by blocking its absorption in the intestine.
Consistent with this hypothesis, previous studies demonstrated that a high-cholesterol diet reduced CYP7A1 mRNA levels and enzymatic activity in the livers of African Green monkeys, a species that was studied because of its similarities to humans in lipoprotein and cholesterol metabolism (2). Rudel et al. (2) showed that this decrease in bile acid production was accompanied by a reduction in intestinal cholesterol absorption. Similar reductions in CYP7A1 mRNA and enzymatic activity after cholesterol feeding have been reported in other species, including hamsters and rabbits (3, 24). To date, little is known about the regulation of hCYP7A1 by cholesterol, and the overall response to dietary cholesterol consumption appears to be highly variable (26, 27, 43, 44, 45, 46, 47). However, there is evidence that bile acid synthesis does not increase and, in some individuals, the fraction of cholesterol absorbed decreases with increasing dietary cholesterol (26, 27, 44, 45).
Whereas rodents appear to cope with excess cholesterol by stimulating its conversion to bile acids for excretion from the body, African Green monkeys and perhaps other species, including humans, may have evolved an alternate strategy, in which the absorption of cholesterol in the intestine is reduced through decreases in bile acid production. These species differences may reflect the amount of cholesterol typically ingested in the diet, with primates having evolved on a lower cholesterol diet. Ultimately, the differences in the regulation of CYP7A1 may contribute to the propensity of humans and other species to develop hypercholesterolemia and other adverse events such as the formation of gall stones as a consequence of a high-cholesterol diet.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Primary Culture of Rat and Human Hepatocytes and Northern Blot Analysis
Primary cultures of rat hepatocytes were prepared as described elsewhere (49). After isolation, hepatocytes were washed in DMEM supplemented with 5% fetal bovine serum, 1 µM dexamethasone, 4 µg/ml insulin, 50 U/ml penicillin, 50 µg/ml streptomycin, and 1.5 x 106 cells seeded into six-well plates coated with Matrigel (Becton Dickinson and Co., Franklin Lakes, NJ). Cells were allowed to attach for 4 h and thereafter maintained in serum-free Williams’ E medium containing 100 nM dexamethasone, 50 U/ml penicillin, 50 µg/ml streptomycin, and insulin-transferrin-selenium (Invitrogen). Primary human hepatocytes were obtained from BioWhittaker, Inc. (Walkersville, MD) and were similarly maintained in serum-free Williams’ E medium containing the supplements outlined above. Subsequently, cells were maintained and treated exactly as previously described (9). Total RNA was isolated and 10 µg resolved on a 1% agarose/2.2 M formaldehyde denaturing gel and transferred to a nylon membrane (Hybond N+, Pharmacia Biotech, Piscataway, NJ). Blots were sequentially hybridized with 32P-labeled cDNAs corresponding to hCYP7A1 (bases 99–1564, GenBank accession no. M93133), hSHP (GenBank accession no. L76571), and hSREBP-1 (bases 403-1204, GenBank accession no. NM 004176), or rat CYP7A1 (bases 235–460, GenBank accession no. J05460), mouse SHP (bases 30–783, GenBank accession no. L76567), mouse SREBP-1 (bases 969-1645, GenBank accession no. AF374266). To ensure equal loading of RNA samples, the blots were probed with radiolabeled cDNA corresponding to the rat 18S rRNA (bases 293–970, GenBank accession no. X01117). The relative signal intensity for Northern blots was determined using a PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA).
Plasmid Constructs
The mammalian expression vectors pcDNA3-hLXR and pcDNA3-hRXR were generated by subcloning the hLXR and hRXR open-reading frames from pSG5-hLXR and pSG5-hRXR (14), respectively, into pcDNA3.1(+) (Invitrogen). Preparation of the hSHP-luciferase reporter gene construct pGL3-hSHP-571 was previously described (9). 5'-Deletion mutants of this construct, namely pGL3-hSHP-413, pGL3-hSHP-288, pGL3-hSHP-266, and pGL3-hSHP-105, which contain bases -413 to +10, -288 to +10, -266 to +10, and -105 to +10, respectively, of the hSHP promoter inserted into the BglII site of the promoterless luciferase reporter vector pGL3-Basic were generated by PCR. Site-directed mutagenesis of the putative LXRE in the hSHP promoter was performed using the Transformer mutagenesis system (CLONTECH Laboratories, Inc., Palo Alto, CA) with the LXRE (bases -294 to -258, 5'-CCTGAGTTAATGttCTTGTTTAggCACTTGAGTCATC). Mutated constructs were verified to be free of nonspecific base changes by sequencing. pß-actin-SPAP, an expression vector containing the human secreted placental alkaline phosphatase (SPAP) cDNA under the control of ß-actin promoter, was used as an internal control in all transfections.
Transient Transfection Assays
HEK293 cells were maintained in MEM containing 10% fetal bovine serum (Irvine Scientific, Santa Ana, CA), 50 U/ml penicillin, and 50 µg/ml streptomycin. Transient transfections were performed in 96-well plates using the FuGene6 transfection reagent (Roche Molecular Biochemicals, Indianapolis, IN) according to the manufacturer’s instructions. Typically, transfection mixes contained 10 ng SHP reporter gene, 2 ng pß-actin-SPAP as an internal control, 5 ng pcDNA3-hLXR, and 3 ng pcDNA3-hRXR. The final amount of plasmid DNA was adjusted to 80 ng with pBluescript II SK(+) (Stratagene, La Jolla, CA).
EMSAs
EMSAs were performed as described elsewhere (9). Competitor oligonucleotides were added at 25-, 100-, or 500-fold molar excess. The binding reactions were resolved on a preelectrophoresed 0.25x Tris-borate-EDTA, 4% polyacrylamide gel at room temperature. Human LXR and RXR proteins were synthesized from pSG5-hLXR and pSG5-RXR, respectively, using the TNT T7-coupled reticulocyte system (Promega Corp., Madison, WI). The following double-stranded oligonucleotides were used as probes and competitors in EMSA: rat CYP7A1 DR4, 5'-AGCTCTTTGGTCACTCAAGTTCAAGT-3'; hSHP DR4, 5'-AGCTTAATGACCTTGTTTATCCACTT-3'.
RT-PCR Analysis
HepG2 cells were grown in phenol red-free DMEM supplemented with 10% (vol/vol) charcoal dextran-stripped fetal bovine serum, 100 U/ml of penicillin, and 0.01% streptomycin. For transfection assays, confluent cells grown in six-well plates were transfected with 1 µg of either cytomegalovirus flag-hSHP or cytomegalovirus-flag plasmid (Stratagene) using Lipofectamine 2000 (Invitrogen) as directed by the manufacturer. Total RNA was isolated at 24–36 h after transfection and subjected to RT-PCR analysis. Total RNA was isolated using Trizol (Life Technologies, Gaithersburg, MD), and cDNA was synthesized using oligo deoxythymidine and reverse transcriptase. hCYP7A1 and hSHP were measured by semiquantitative RT-PCR. ß-Actin served as an internal control for the RT-PCR analysis. The amplification of these mRNAs was linear up to 25–30 cycles of PCR (data not shown). ß-Actin, CYP7A1, and SHP were amplified by 22, 28, and 25 cycles of PCR, respectively. The following primers were used to amplify CYP7A1, SHP, and ß-actin: CYP7A1 forward primer, 5'-CTAAGGAGGATTTCACTTGC-3'; CYP7A1 reverse primer, 5'-ACTGGTCCAAAGGTGGACAT-3'; SHP forward primer, 5'-CAAGAAGATTCTGCTGGAGG-3'; SHP reverse primer, 5'-GGATGTCAACATCTCCAATG-3'; ß-actin forward primer, 5'-GTCATCACCATTGGCAATGAG-3'; ß-actin reverse primer, 5'-CGTCATACTCCTGCTTGCTG-3'. The sizes of the CYP7A1, SHP, and ß-actin in PCR products were 350, 390, and 350 bp, respectively.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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-hydroxylase; FXR, farnesoid X receptor; h, human; HEK293, human embryonal kidney cell line; LXR, liver X receptor; LXRE, LXR response element; RXR, 9-cis-retinoic acid receptor-; SHP, short heterodimer partner; SPAP, secreted placental alkaline phosphatase; SREBP-1, sterol-regulatory element-binding protein 1; tk, thymidine kinase. Received for publication July 15, 2002. Accepted for publication December 6, 2002.
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Y. Honjo, S. Sasaki, Y. Kobayashi, H. Misawa, and H. Nakamura 1,25-dihydroxyvitamin D3 and its receptor inhibit the chenodeoxycholic acid-dependent transactivation by farnesoid X receptor. J. Endocrinol., March 1, 2006; 188(3): 635 - 643. [Abstract] [Full Text] [PDF]
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Y. Wang, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold Downregulation of liver X receptor-{alpha} in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines J. Lipid Res., November 1, 2005; 46(11): 2377 - 2387. [Abstract] [Full Text] [PDF]
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F. Y. Lee, H. R. Kast-Woelbern, J. Chang, G. Luo, S. A. Jones, M. C. Fishbein, and P. A. Edwards {alpha}-Crystallin Is a Target Gene of the Farnesoid X-activated Receptor in Human Livers J. Biol. Chem., September 9, 2005; 280(36): 31792 - 31800. [Abstract] [Full Text] [PDF]
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 S W C van Mil, R H J Houwen, and L W J Klomp Genetics of familial intrahepatic cholestasis syndromes J. Med. Genet., June 1, 2005; 42(6): 449 - 463. [Abstract] [Full Text] [PDF]
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A. Jahan and J. Y. L. Chiang Cytokine regulation of human sterol 12{alpha}-hydroxylase (CYP8B1) gene Am J Physiol Gastrointest Liver Physiol, April 1, 2005; 288(4): G685 - G695. [Abstract] [Full Text] [PDF]
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A. Honda, G. Salen, Y. Matsuzaki, A. K. Batta, G. Xu, T. Hirayama, G. S. Tint, M. Doy, and S. Shefer Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis J. Lipid Res., February 1, 2005; 46(2): 287 - 296. [Abstract] [Full Text] [PDF]
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J.-Y. Kim, H.-J. Kim, K. T. Kim, Y.-Y. Park, H.-A Seong, K. C. Park, I.-K. Lee, H. Ha, M. Shong, S. C. Park, et al. Orphan Nuclear Receptor Small Heterodimer Partner Represses Hepatocyte Nuclear Factor 3/Foxa Transactivation via Inhibition of Its DNA Binding Mol. Endocrinol., December 1, 2004; 18(12): 2880 - 2894. [Abstract] [Full Text] [PDF]
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Y. Liang, X.-C. Jiang, R. Liu, G. Liang, T. P. Beyer, H. Gao, T. P. Ryan, S. Dan Li, P. I. Eacho, and G. Cao Liver X Receptors (LXRs) Regulate Apolipoprotein AIV-Implications of the Antiatherosclerotic Effect of LXR Agonists Mol. Endocrinol., August 1, 2004; 18(8): 2000 - 2010. [Abstract] [Full Text] [PDF]
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H.-J. Kim, J.-Y. Kim, J.-Y. Kim, S.-K. Park, J.-H. Seo, J. B. Kim, I.-K. Lee, K.-S. Kim, and H.-S. Choi Differential Regulation of Human and Mouse Orphan Nuclear Receptor Small Heterodimer Partner Promoter by Sterol Regulatory Element Binding Protein-1 J. Biol. Chem., July 2, 2004; 279(27): 28122 - 28131. [Abstract] [Full Text] [PDF]
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K. R. Steffensen and J.-A. Gustafsson Putative Metabolic Effects of the Liver X Receptor (LXR) Diabetes, February 1, 2004; 53(90001): S36 - 42. [Abstract] [Full Text]
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D.-J. Shin, J. A. Campos, G. Gil, and T. F. Osborne PGC-1{alpha} Activates CYP7A1 and Bile Acid Biosynthesis J. Biol. Chem., December 12, 2003; 278(50): 50047 - 50052. [Abstract] [Full Text] [PDF]
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K. Lai, D. C. Harnish, and M. J. Evans Estrogen Receptor {alpha} Regulates Expression of the Orphan Receptor Small Heterodimer Partner J. Biol. Chem., September 19, 2003; 278(38): 36418 - 36429. [Abstract] [Full Text] [PDF]
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