| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
GlaxoSmithKline (P.D., E.N.), Cardiovascular & Urogenital Center of Excellence for Drug Discovery, 91951 Les Ulis, France; GlaxoSmithKline, High Throughput Biology (C.M.G., B.G.), and Gene Interference Group (J.E.B.), Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Philippe Delerive, GlaxoSmithKline Research and Development, Cardiovascular and Urogenital Diseases Center of Excellence for Drug Discovery, 25 Avenue du Quebec, 91951 Les Ulis, France. E-mail: pxd14884{at}gsk.com.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
-position and is catalyzed by CYP7A1. Expression of CYP7A1 is subject to feedback repression by bile acids and a bile acid response element has been identified in the 5'-flanking region of the gene (3). Multiple, redundant signaling cascades converge on this highly conserved element that is a well-documented binding site for members of the nuclear receptor superfamily of ligand activated transcription factors, notably, liver receptor homolog-1 (LRH-1, NR5A2) and hepatocyte nuclear factor-4 (HNF-4; NR2A1) (3).
LRH-1 is the mammalian homolog of the Drosophila fushi tarazu F1 receptor (FTZ-F1; NR5A3) and, like FTZ-F1, binds its cognate target sequence [5'-(Py)CAAGG(Py)C(Pu)-3'] as a monomer (4). It is highly expressed in ovary, liver, intestine, and pancreas (4, 5, 6). Nitta et al. (5) reported that LRH-1 bound and activated the CYP7A1 promoter through the bile acid response element, suggesting a role in the bile acid-dependent repression of this gene. It is now known that bile acids suppress transcription of the CYP7A1 gene through a cascade of nuclear receptors, which includes the bile acid receptor FXR (farnesoid X receptor; NR1H4), the transcriptional repressor small heterodimer partner (SHP; NR0B2), and LRH-1 (7, 8). Thus, bile acids activate FXR, which binds to a response element in the SHP promoter as a heterodimer with the 9-cis retinoic acid receptor (RXR; NR2B1) and induces expression of the gene. SHP, in turn, interacts with LRH-1 and strongly suppresses its transcriptional activity (7, 8). Studies performed in mice harboring a disrupted Shp gene confirm the importance of the FXR-SHP-LRH-1 cascade in suppression of Cyp7a1; however, they also demonstrate the existence of SHP-independent pathways (9, 10). In addition to CYP7A1, LRH-1 is implicated in the regulation of key transcription factors involved in hepatic and pancreatic development, such as the hepatic nuclear factors HNF-3ß, HNF-4, and HNF-1 (11). Recently, LRH-1 was shown to regulate expression of aromatase (CYP19) in ovarian and adipose tissue (12) and adiponectin in adipocytes (13). Moreover, LRH-1 is reported to regulate expression of CETP (14) and SR-BI (6), thereby implicating this receptor in HDL remodeling and cholesterol transport.
Intriguingly, a number of clinical studies have documented an inverse correlation between circulating levels of APOAI or HDL and bile acids. Thus, patients receiving the enteric bile acid sequestrant cholestyramine had elevated levels of serum APOAI (15). Conversely, patients with progressive familial intrahepatic cholestasis or biliary atresia, conditions that result in systemic and hepatic accumulation of bile acids, exhibit reduced serum APOAI compared with healthy individuals (16). Furthermore, in similarity to CYP7A1, synthetic and naturally occurring FXR ligands suppress expression of APOAI in primary cultures of human hepatocytes and in transgenic mice harboring a complete human APOAI locus (17). Moreover, the bile acid response element characterized by Staels and co-workers (17) is highly homologous to a previously characterized LRH-1 binding motif in the prototypic LRH-1 target gene -fetoprotein (4). Taken together, these observations suggested that the FXR-SHP-LRH-1 cascade may also play a role in the regulation of the APOAI gene. Therefore, in this study we examined the role of LRH-1 in the regulation of APOAI expression. We establish that APOAI is directly regulated by LRH-1 and demonstrate interplay between multiple nuclear receptors in the regulation of this gene. These results suggest that LRH-1 plays a key role in cholesterol homeostasis.
|
RESULTS AND DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
). Western immunoblot analysis revealed that this inhibition occurred also at the protein level and that the nonsilencing control siRNA does not affect endogenous LRH-1 protein expression (Fig. 1B). As a control, ß-actin protein levels were not modified after siRNA transfection (Fig. 1B). Interestingly, we found that APOAI gene expression was significantly decreased by a siRNA targeting LRH-1 expression (
60% reduction). Furthermore, this inhibition appeared to be dose dependent (Fig. 1C). This effect appeared to be specific because a second siRNA targeting LRH-1 mRNA induced a similar down-regulation of APOAI gene expression (data not shown). In addition, SR-BI, an established LRH-1 target gene (6), was down-regulated in cells transfected with the siRNA targeting LRH-1 expression, whereas APOB gene expression was not affected demonstrating the specificity of this effect (Fig. 1C).
|
). Furthermore, the LRH-1-dependent activation of this promoter was completely inhibited by overexpression of SHP. By contrast, a control virus expressing green fluorescent protein (Ad-GFP) failed to activate this reporter gene construct. This result indicates that the adenovirus delivers a functional LRH-1 protein. Next, the influence of LRH-1 was tested on APOAI transcription in HepG2 cells. Ectopic expression of LRH-1 resulted in a robust (more than 5-fold) induction of APOAI mRNA in comparison to cells infected with the control virus (Fig. 2B). In parallel, expression of the CYP7AI gene was significantly (20-fold) increased by LRH-1 overexpression. Again, these data suggest that LRH-1 regulates APOAI gene transcription in human liver cells. To determine whether LRH-1 regulates APO AI gene expression in rodents, C57BL6 mice were injected with Ad-mLRH1 or Ad-GFP. Forty-eight hours later, hepatic LRH-1, CYP7A1, and APOAI mRNA levels were quantified by Taqman analysis (Fig. 2C). As expected, CYP7A1 was significantly induced by LRH-1 overexpression (4-fold). By contrast, APOAI gene expression was not affected by LRH-1, suggesting that LRH-1-mediated APOAI gene regulation occurs in a species-specific manner.
|
). A highly reproducible maximal induction of 3-fold was observed in this setting. By contrast, LRH-1 cotransfection in CV-1 cells led to a dramatic increase in of APOAI promoter activity (up to 11-fold). The more robust response observed in the CV-1 cells most likely reflects the lack of LRH-1 protein expression and lower basal activity of the APOAI-luciferase reporter observed in these cells (Fig. 3C). Taken together, these results suggested that LRH-1 controls APOAI expression at the transcriptional level. Interestingly, the murine APOAI promoter was also responsive to LRH-1, albeit, to a much lesser extent than the human (Fig. 3D). This weaker inducibility of the murine promoter construct could be explained by the relatively high basal activity (30-fold higher) of the mouse compared with the human promoter (data not shown). This is likely to be explained by regulatory elements located in the distal promoter because the proximal region is well conserved between species. Furthermore, those results explain, at least in part, the lack of APOAI induction in mice where LRH-1 has been overexpressed (Fig. 2C
). Interestingly, such species-specific APOAI gene regulation have already been reported for another member of the nuclear receptor superfamily, namely HNF4, that plays a key role in APOAI gene transcription in human but not in mouse liver cells (22).
|
). Mutation of the putative LRH-1 response element almost completely abolished the LRH-1-dependent activation, demonstrating that this site is indeed a functional LRH-1 response element capable of conferring responsiveness on the APOAI promoter (Fig. 4). Next, EMSAs using in vitro-translated LRH-1 protein were performed to examine whether LRH-1 could directly bind to this response element. When incubated with recombinant LRH-1, a radiolabeled probe corresponding to the –133 site (apoAI-133; Fig. 5A) produced a shifted protein/DNA complex. This band was efficiently competed by the wild-type but not by the mutant (apoAI-133mut) unlabeled oligonucleotide (Fig. 5B), indicating that LRH-1 binds to this response element in a specific manner in vitro. To determine whether LRH-1 associates with the human APOAI promoter in vivo, we performed chromatin immunoprecipitation (ChIP) assay in HepG2 cells (Fig. 5C). LRH-1 binding was observed in the proximal APOAI promoter that contains the LRH-1 response element, but not, in the more distal region as determined by PCR amplification (Fig. 5C). This result indicates that LRH-1 binds to the APOAI promoter in vivo. Taken together, these results indicate that LRH-1 regulates APOAI gene transcription via a response element located in the vicinity of the B site as originally defined by Papazafiri et al. (19) and subsequently characterized as a negative bile acid response element by Claudel et al. (17).
|
|
). The inverse correlation between APOAI and SHP expression in response to FXR agonists indirectly supports the existence of a SHP-dependent mechanism of APOAI repression. Transient transfection of increasing amounts of SHP led to a dose-dependent inhibition of the human APOA1 promoter activity in HepG2 cells (Fig. 6B). By contrast, the mutated construct, where the LRH-1 binding site has been disrupted, was not affected by SHP overexpression, suggesting that SHP-mediated APOAI promoter occurs in an LRH-1-dependent manner (Fig. 6B). Importantly, this construct has a significantly lower basal promoter activity, which is consistent with the role of LRH-1 in contributing to APOAI gene regulation. Taken together, these findings suggest that the suppression of APOAI by FXR activators is most likely mediated by an FXR-SHP-LRH-1 cascade as described for other bile acid-responsive genes.
|
-hydroxylase required for cholic acid production (5, 7, 8). By regulating the expression of this cohort of genes LRH-1 appears to play a central role in the elimination of cholesterol from the body.
The molecular mechanisms underlying expression of the APOAI gene have received considerable attention (see Ref. 20 for review). APOAI transcription has been show to be modulated by various nuclear receptors, such as apolipoprotein regulatory protein-1 (ARP-1; NR2F2) (21), HNF-4 (22), and peroxisome proliferator-activated receptor (PPAR, NR1C1) (23). More recently, bile acids, which are naturally occurring ligands for the nuclear receptor FXR (24, 25), have been shown to inhibit APOAI gene expression in vitro and in vivo (17, 26). Srivastava and co-workers (26) showed that cholic acid regulates APOAI at the level of transcription and suggested that the bile acid-dependent induction of ARP-1, a negative regulator of APOAI expression, was responsible for this suppression. Subsequently, Claudel and co-workers (17) identified a novel bile acid response element in the vicinity of the B site described by Papazafiri et al. (19) and suggested that ligand-activated FXR binds to this site as a monomer and suppresses APOAI expression. Here, we mapped this B site as a functional LRH-1 response element using promoter analysis and EMSA (Figs. 4 and 5). Moreover, we showed using ChIP assays that LRH-1 binds to the human APO AI promoter in vivo (Fig. 5C). Because FXR has been shown to inhibit APOAI promoter activity through this site, we propose that FXR negatively regulates APOAI transcription by inducing SHP which, in turn, trans-represses LRH-1 activity. A similar mechanism has been proposed for the bile acid-dependent suppression of the CYP7A1, CYP8B1, and ASBT genes. In line with this hypothesis, we also showed that SHP represses APOAI promoter activity in a LRH-1-dependent manner (Fig. 6B). Although these studies strongly suggest that SHP is key regulator of APOAI, we cannot rule out the involvement of SHP-independent mechanisms in APOAI gene regulation, as suggested for CYP7A1. Further studies will be necessary to determine which mechanism(s) are biologically relevant in vivo.
In conclusion, this study led to the identification of LRH-1 as a novel modulator of APOAI gene and reinforces the concept that LRH-1 plays a crucial role in bile acid biosynthesis but also in reverse cholesterol transport.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Plasmids
The plasmids, pSG5-LRH-1, pSG5-SHP, and pSG5-HNF4 have been previously described (7). The pSG5 plasmid, was purchased from Stratagene (La Jolla, CA). The human and mouse APOAI promoter constructs (–1162+234) were obtained by PCR amplification using human and mouse genomic DNA (CLONTECH, Palo Alto, CA) as template. The resulting PCR products were inserted as a BglII/HindIII fragment into pGL3 basic vector (Promega, Madison, WI) yielding human Apo AI-Luc and mouse Apo AI-Luc, respectively. The mutation of the LRH-1 binding site within human Apo AI promoter was obtained by site-directed mutagenesis (Stratagene) using the following oligonucleotides: 5'-CAGAGCTGATCCTTTAACTCTTAAG-3' and 5'-CTTAAGAGTTAAAGGATCAGCTCTG-3'. All constructs were verified by DNA sequence analysis.
Transient Transfection Assays
HepG2 and CV1 cells, plated in 24-well plates at 50–60% confluence in basic Eagle’s medium supplemented with 10% FCS, were transiently transfected with reporter and receptor expression plasmids using Fugene 6 reagent (Roche Molecular Biochemicals, Indianapolis, IN) as indicated in the figure legends. The pSEAP2 expression plasmid (CLONTECH) was cotransfected to assess transfection efficiency. Forty-eight hours post transfection, cells were collected and assayed for luciferase and alkaline phosphatase activities. All experiments were repeated at least three times. Results are expressed as mean ± SD.
RNA Interference
Twenty-one-nucleotide RNA oligonucleotides directed against human LRH-1 were obtained from Dharmacon (Lafayette, CO). QIAGEN (Valencia, CA) provided the nonsilencing control siRNA. The siRNA sequence targeting LRH-1 (GenBank accession no. AB019246) corresponds to the coding region (nucleotides 1199–1219) relative to the first nucleotide of the start codon. HepG2 cells (40% confluence) were transfected with siRNAs by using TransIt-TKO reagent (Mirus, Madison, WI) following the manufacturer’s instructions. Twenty-four hours post transfection, cells were refed with fresh medium for additional 24 h.
RNA Analysis
Total cellular RNA was extracted using TRIZOL (Invitrogen Life Technologies, Carlsbad, CA). Real-time quantitative PCR (RT-QPCR) assays were performed using an Applied Biosystems (Foster City, CA) 7900 sequence detector. Total RNA (1 µg) was reverse transcribed with random hexamers using Taqman reverse-transcription reagents kit (Applied Biosystems) following the manufacturer’s protocol. RNA expression levels were determined by Sybr green assays as described. 18SrRNA transcript was used as an internal control to normalize the variations for RNA amounts. Gene expression levels are expressed relative to 18S rRNA. Apo AI, Apo B, SR-BI, SHP, LRH-1 and CYP7A1 mRNA levels were measured using the following oligonucleotides: For 18S: 5'-GGGAGCCTGAGAAACGGC-3' and 5'-GGGTCGGGAGTGGGTAATTT-3'; for APOAI: 5'-CTCGGCATTTCTGGCAGCAA-3' and 5'-ACGTACACAGTGGCCAGGTCCTT-3'; for Apo B: 5'-TTCTGCCACATGCTTCCTCTT-3' and 5'-GACCCGCCCCTTGTCAA-3'; for SR-BI: 5'-TCCTCCGGGTCTTAAAGGTGAT-3' and 5'-GGCCTTTTGGTCCAGAATTTC-3'; for SHP: 5'-CGCCCTATCATTGGAGATGT-3' and 5'-AGGAGCATTGG GTCACCTC-3'; for LRH-1: 5'-TGCAGGCTGAAGAATACCTCT-3' and 5'-GCATGCAACATTTCAATGAG-3'; for CYP7A1: 5'-CCCTTTGGATCGGGAGCTA-3' and 5'-AGCTCCAATTC AAAATAAGAAAGCAT-3'.
Adenovirus Generation
The recombinant adenovirus (Ad-GFP and LRH-1) was obtained by homologous recombination in Escherichia coli (27) after insertion of the cDNAs into pAdCMV2. Viral stocks were created as previously described (28). Viral titers were determined by a plaque assay on 293 cells and expressed as plaque-forming units per milliliter. Cells were infected, in most of the experiments, at a MOI of 50 viral particles per cell, by adding virus stocks directly to the HepG2 culture medium.
Western Blot Analysis
Protein extracts were fractionated on 10% polyacrylamide gel under reducing conditions (sample buffer containing 10 mM dithiothreitol, and transferred onto nitrocellulose membranes). LRH-1 protein was visualized by probing the membrane with a goat polyclonal LRH-1 antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA; sc-6062). After incubation with a secondary peroxidase-conjugated antibody, signals were detected by chemiluminescence (Amersham Biosciences, Buckinghamshire, UK).
EMSA
Double-stranded oligonucleotides were end-labeled with 
32P-ATP using T4 polynucleotide kinase according to standard procedures. In vitro-translated proteins (2 µl) were incubated with 100,000 cpm of labeled probe for 20 min at room temperature in 20 µl of buffer containing 10 mM Tris (pH 7.5), 50 mM NaCl, 1 mM dithiothreitol, 1 mM EDTA, 5% glycerol, 0.3 µg BSA and 2 µg of poly (deoxyinosine-deoxycytosine). DNA/protein complexes were analyzed by electrophoresis in a 5% nondenaturing polyacrylamide gel with 0.5x Tris-borate-EDTA buffer. The gel was then dried and exposed at –80 C for autoradiography.
ChIP
ChIP assays were performed essentially as previously described (29). Briefly, 50 x 106 of HepG2 cells were cross-linked for 30 min at 4 C by adding a 11% formaldehyde-containing solution. Cross-linking was stopped by adding glycine to a final concentration of 125 mM for 5 min. Then, cells were rinsed with PBS, harvested and centrifuged at 600 x g for 5 min at 4 C. Pellets were resuspended in lysis buffer [50 mM HEPES-KOH (pH 8.0), 1 mM EDTA, 0.5 mM EGTA, 140 mM NaCl, 10% glycerol, 0.5% Nonidet P-40, 0.25% Triton X-100, 1 mM phenylmethylsulfonyl fluoride (PMSF), and leupeptin/pepstatin A/aprotinin 5 µg/ml each] and rotated for 10 min at 4 C. The nuclei were collected by centrifugation and resuspended in 10 ml wash buffer [10 mM Tris-HCl (pH 8), 1 mM EDTA, 0.5 mM EGTA, 200 mM NaCl, 1 mM PMSF, and leupeptin/pepstatin A/aprotinin 5 µg/ml each] and rotated again. Washed nuclei were centrifuged and resuspended in 1x RIPA buffer [10 mM Tris-HCl (pH 8), 1 mM EDTA, 0.5 mM EGTA, 140 mM NaCl, 1% Triton X-100, 0.1% sodium dodecyl sulfate, 0.1% Na-deoxycholate, 1 mM PMSF, and leupeptin/pepstatin A/aprotinin 5 µg/ml each] and subsequently sonicated leading to the generation of DNA fragment sizes of 0.3–1.5 kb. Samples were cleared by centrifugation at 16,000 x g for 10 min at 4 C. Ten percent of the cleared supernatant was used as input and the remaining volume was immunoprecipitated using a goat LRH-1 polyclonal antibody (8 µg/ml; Santa Cruz Biotechnology, Inc.; sc-6062). After extensive washings, proteins were digested by adding proteinase K (100 µg/ml) and placed at 55 C for 3 h followed by 6 h at 65 C to reverse cross-links. DNA was extracted by standard procedure and pellets were resuspended in Tris-EDTA buffer. The human proximal and distal APOAI promoter regions were PCR-amplified using the following oligonucleotides: APOAI_DF 5'-TAACTTGCCCACGATCTTCC-3' and APOAI DR 5'-CTTAGATTGAAGACGTCTCCC-3', APOAI_PF 5'-TGCAAGCCTGCAGACACT-3' and APOAI_PR 5'-CTAAGCAGCCAGCTCTTGC-3'. PCRs were analyzed by electrophoresis on a 1% agarose gel.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
, hepatocyte nuclear factor-4; LRH-1, liver receptor homolog-1; MOI, multiplicity of infection; PMSF, phenylmethylsulfonyl fluoride; RT-QPCR, real-time quantitative PCR; SHP, SHP small heterodimer partner; SR-BI, scavenger receptor class B type I. Received for publication March 31, 2004. Accepted for publication June 11, 2004.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
-hydroxylase gene. Proc Natl Acad Sci USA 96:6660–6665, and HNF1 gene promoters. J Biol Chem 276:13136–13144
B by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev 14:2314–2329NURSA Molecule Pages Link:
This article has been cited by other articles:
 |
|
 |
|
  P. Lefebvre, B. Cariou, F. Lien, F. Kuipers, and B. Staels Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation Physiol Rev, January 1, 2009; 89(1): 147 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D J Hausenloy and D M Yellon Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels Postgrad. Med. J., November 1, 2008; 84(997): 590 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Colin, E. Bourguignon, A.-B. Boullay, J.-J. Tousaint, S. Huet, F. Caira, B. Staels, S. Lestavel, J.-M. A. Lobaccaro, and P. Delerive Intestine-Specific Regulation of PPAR{alpha} Gene Transcription by Liver X Receptors Endocrinology, October 1, 2008; 149(10): 5128 - 5135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Masson, M. Qatanani, A. L. Sberna, R. Xiao, J. P. Pais de Barros, J. Grober, V. Deckert, A. Athias, P. Gambert, L. Lagrost, et al. Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice J. Lipid Res., August 1, 2008; 49(8): 1682 - 1691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D J Hausenloy and D M Yellon Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels Heart, June 1, 2008; 94(6): 706 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Song, R. Kaimal, B. Yan, and R. Deng Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression J. Lipid Res., May 1, 2008; 49(5): 973 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Venteclef, A. Haroniti, J.-J. Tousaint, I. Talianidis, and P. Delerive Regulation of Anti-atherogenic Apolipoprotein M Gene Expression by the Orphan Nuclear Receptor LRH-1 J. Biol. Chem., February 15, 2008; 283(7): 3694 - 3701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Mataki, B. C. Magnier, S. M. Houten, J.-S. Annicotte, C. Argmann, C. Thomas, H. Overmars, W. Kulik, D. Metzger, J. Auwerx, et al. Compromised Intestinal Lipid Absorption in Mice with a Liver-Specific Deficiency of Liver Receptor Homolog 1 Mol. Cell. Biol., December 1, 2007; 27(23): 8330 - 8339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Labelle-Dumais, J.-F. Pare, L. Belanger, R. Farookhi, and D. Dufort Impaired Progesterone Production in Nr5a2+/ Mice Leads to a Reduction in Female Reproductive Function Biol Reprod, August 1, 2007; 77(2): 217 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kanayama, M. Arito, K. So, S. Hachimura, J. Inoue, and R. Sato Interaction between Sterol Regulatory Element-binding Proteins and Liver Receptor Homolog-1 Reciprocally Suppresses Their Transcriptional Activities J. Biol. Chem., April 6, 2007; 282(14): 10290 - 10298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Venteclef and P. Delerive Interleukin-1 Receptor Antagonist Induction as an Additional Mechanism for Liver Receptor Homolog-1 to Negatively Regulate the Hepatic Acute Phase Response J. Biol. Chem., February 16, 2007; 282(7): 4393 - 4399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Li, W. Chen, and J. Y. L. Chiang PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine J. Lipid Res., February 1, 2007; 48(2): 373 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors Pharmacol. Rev., December 1, 2006; 58(4): 798 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Venteclef, J. C. Smith, B. Goodwin, and P. Delerive Liver receptor homolog 1 is a negative regulator of the hepatic acute-phase response. Mol. Cell. Biol., September 1, 2006; 26(18): 6799 - 6807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fugier, J.-J. Tousaint, X. Prieur, M. Plateroti, J. Samarut, and P. Delerive The Lipoprotein Lipase Inhibitor ANGPTL3 Is Negatively Regulated by Thyroid Hormone J. Biol. Chem., April 28, 2006; 281(17): 11553 - 11559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-K. Lee, Y.-H. Choi, S. Chua, Y. J. Park, and D. D. Moore Phosphorylation of the Hinge Domain of the Nuclear Hormone Receptor LRH-1 Stimulates Transactivation J. Biol. Chem., March 24, 2006; 281(12): 7850 - 7855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Mooradian, M. J. Haas, and N. C. W. Wong The Effect of Select Nutrients on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I Levels Endocr. Rev., February 1, 2006; 27(1): 2 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Shelness and L. L. Rudel A Role for the Pregnane X Receptor in High-Density Lipoprotein Metabolism Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2016 - 2017. [Full Text] [PDF]
|
|
|
|
|
|
T. Claudel, B. Staels, and F. Kuipers The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2020 - 2030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Masson, L. Lagrost, A. Athias, P. Gambert, C. Brimer-Cline, L. Lan, J. D. Schuetz, E. G. Schuetz, and M. Assem Expression of the Pregnane X Receptor in Mice Antagonizes the Cholic Acid-Mediated Changes in Plasma Lipoprotein Profile Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2164 - 2169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, M. Choi, K. Suino, A. Kovach, J. Daugherty, S. A. Kliewer, and H. E. Xu Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner PNAS, July 5, 2005; 102(27): 9505 - 9510. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
