Research Topics
| Steven KliewerSummaryAffiliation: University of Texas Southwestern Medical Center Country: USA Publications
Research Grants
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Detail Information
Publications
The nuclear pregnane X receptor: a key regulator of xenobiotic metabolismSteven A Kliewer
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
Endocr Rev 23:687-702. 2002..Thus, assays that detect PXR activity will be useful in developing safer prescription drugs...- The nuclear pregnane X receptor regulates xenobiotic detoxificationSteven A Kliewer
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 8594, USA
J Nutr 133:2444S-2447S. 2003..John's wort represents the molecular basis for an important class of drug-drug interactions. Assays that detect PXR activation can now be used to predict and prevent these drug-drug interactions... - Anthrax mounts a nuclear attack on glucocorticoid signalingSteven A Kliewer
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
Trends Pharmacol Sci 24:558-9. 2003..Thus, these findings suggest that glucocorticoid receptor inactivation contributes to anthrax toxicity and raise the possibility of developing new strategies to combat this deadly disease... - Pregnane X receptor: predicting and preventing drug interactionsSteven A Kliewer
Departments of Molecular Biology and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA
Thromb Res 117:133-6; discussion 145-51. 2005 
Cholesterol detoxification by the nuclear pregnane X receptorSteven A Kliewer
Departmens of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA
Proc Natl Acad Sci U S A 102:2675-6. 2005- Fibroblast growth factor 21: from pharmacology to physiologySteven A Kliewer
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 73590 9041, USA
Am J Clin Nutr 91:254S-257S. 2010..This article highlights recent advances in our understanding of FGF21's pharmacologic and physiologic actions... - Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptorsLinda B Moore
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
Mol Endocrinol 16:977-86. 2002..Modeling studies suggest that the H1-3 insert contributes to the promiscuity of the PXRs by facilitating the unwinding of helices-6 and -7, thereby expanding the ligand binding pocket... - Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxificationJodi M Maglich
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina, USA
Mol Pharmacol 62:638-46. 2002..These findings underscore the importance of these two nuclear receptors in defending the body against a broad array of potentially harmful xenobiotics... - Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptorBryan Goodwin
Nuclear Receptor Discovery Research, GlaxoSmithKline Inc, Five Moore Drive, Research Triangle Park, NC 27709, USA
Proc Natl Acad Sci U S A 100:223-8. 2003..In addition, this study demonstrates that animal models with alterations in gene expression can be used to identify endogenous ligands for orphan nuclear receptors... - Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesisJason A Holt
Nuclear Receptor Discovery Research, High Throughput Biology, Gene Interference, Transgenics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
Genes Dev 17:1581-91. 2003..This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver... - Regulation of cyp3a gene transcription by the pregnane x receptorBryan Goodwin
Nuclear Receptor Systems Research, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA
Annu Rev Pharmacol Toxicol 42:1-23. 2002..On the other hand, PXR agonists may prove useful in the treatment of diseases in which toxic metabolites accumulate, such as cholestatic liver disease... - CYP3A induction by N-hydroxyformamide tumor necrosis factor-alpha converting enzyme/matrix metalloproteinase inhibitors use of a pregname X receptor activation assay and primary hepatocyte culture for assessing induction potential in humansTimothy K Tippin
Drug Metabolism and Pharmacokinetics Department, Metabolic and Viral Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
Drug Metab Dispos 31:870-7. 2003..In conclusion, GW3333 is a potential inducer of CYP3A expression in vivo in humans, but other N-hydroxyformamides are less likely to induce CYP3A... - Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasisTakeshi Inagaki
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
Cell Metab 2:217-25. 2005..These studies define FGF15 and FGFR4 as components of a gut-liver signaling pathway that synergizes with SHP to regulate bile acid synthesis... - FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation responseMatthew J Potthoff
Department of Pharmacology, Howard Hughes Medical Institute, Advanced Imaging Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Proc Natl Acad Sci U S A 106:10853-8. 2009..These results reveal an unexpected relationship between FGF21 and PGC-1alpha and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation... - Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptorSteven A Kliewer
Nuclear Receptor Discovery Research, GlaxoSmithKline, 5 Moore Drive, Room V118 1B, Research Triangle Park, NC 27709, USA
J Lipid Res 43:359-64. 2002.... - PXR, CAR and drug metabolismTimothy M Willson
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA
Nat Rev Drug Discov 1:259-66. 2002..In this review, we provide an examination of the roles of PXR and CAR as xenobiotic sensors, and discuss the application of this knowledge to toxicological screening in drug discovery... - FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorptionDiana Jung
Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9050, USA
J Lipid Res 48:2693-700. 2007..These findings suggest that FXR agonists or FGF15 could be used therapeutically to interrupt the cycle of excessive bile acid production in patients with bile acid malabsorption... - Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptorTakeshi Inagaki
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Proc Natl Acad Sci U S A 103:3920-5. 2006.... - Use of in vitro pregnane X receptor assays to assess CYP3A4 induction potential of drug candidatesStacey A Jones
Department of Nuclear Receptor Functional Analysis, High Throughput Biology, GlaxoSmithKline, Inc, Research Triangle Park, North Carolina 27709, USA
Methods Enzymol 357:161-70. 2002 - Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesisYoun Kyoung Lee
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9041, USA
Mol Endocrinol 22:1345-56. 2008..Taken together, these data reveal a broad role for LRH-1 in regulating bile acid homeostasis but demonstrate that LRH-1 is either not involved in the feedback regulation of bile acid synthesis or is compensated for by other factors... - Nuclear receptor regulation of genes involved in bile acid metabolismJohn T Moore
GlaxoSmithKline, Research Triangle Park, NC 27709, USA
Crit Rev Eukaryot Gene Expr 12:119-35. 2002..These studies highlight the dynamic interplay between nuclear receptors in the regulation of specific metabolic pathways... - Regulation of bile acid synthesis by fat-soluble vitamins A and DDaniel R Schmidt
Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9050, USA
J Biol Chem 285:14486-94. 2010..These results reveal an unexpected link between the intake of fat-soluble vitamins A and D and bile acid metabolism, which may have evolved as a means for these dietary vitamins to regulate their own absorption... - Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21Takeshi Inagaki
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Cell Metab 5:415-25. 2007..These findings demonstrate an unexpected role for the PPARalpha-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation... - Inhibition of growth hormone signaling by the fasting-induced hormone FGF21Takeshi Inagaki
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Cell Metab 8:77-83. 2008..Chronic exposure to FGF21 markedly inhibits growth in mice. These data suggest a central role for FGF21 in inhibiting growth as part of its broader role in inducing the adaptive response to starvation... - Partial resistance to peroxisome proliferator-activated receptor-alpha agonists in ZDF rats is associated with defective hepatic mitochondrial metabolismSanthosh Satapati
The Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Diabetes 57:2012-21. 2008..The purpose of this study is to determine whether abnormal mitochondrial metabolism plays a role in the dysregulation of both hepatic fat and glucose metabolism during diabetes... - Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalphaH Eric Xu
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
Nature 415:813-7. 2002..Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors... - Nuclear receptors. I. Nuclear receptors and bile acid homeostasisBryan Goodwin
Nuclear Receptor Discovery Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA
Am J Physiol Gastrointest Liver Physiol 282:G926-31. 2002..A greater understanding of these receptors should afford novel opportunities for therapeutic intervention in chronic diseases such as cholestasis and dyslipidemia... - Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genesJodi M Maglich
Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA
J Biol Chem 278:17277-83. 2003..Notably, CAR and PXR activators differentially regulated the expression of several genes, demonstrating that these two nuclear receptors subserve overlapping but distinct biological functions in human hepatocytes... - Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasisYaping Liu
Nuclear Receptor Functional Analysis, High Thruput Biology, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA
J Clin Invest 112:1678-87. 2003..The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease... - Cell-free ligand binding assays for nuclear receptorsStacey A Jones
GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA
Methods Enzymol 364:53-71. 2003.... - Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alphaBryan Goodwin
Nuclear Receptor Discovery Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA
Mol Endocrinol 17:386-94. 2003..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... - Regulation of cholesterol homeostasis by the liver X receptors in the central nervous systemKarl D Whitney
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA
Mol Endocrinol 16:1378-85. 2002.... - Identification of a hormonal basis for gallbladder fillingMihwa Choi
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
Nat Med 12:1253-5. 2006..These studies demonstrate that gallbladder filling is actively regulated by an endocrine pathway and suggest a postprandial timing mechanism that controls gallbladder motility... - Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21Hiroshi Kurosu
Departments of Pathology and Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA
J Biol Chem 282:26687-95. 2007..We conclude that the expression of betaKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21... - Weaving betaKlotho into bile acid metabolismAntonio Moschetta
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA
J Clin Invest 115:2075-7. 2005..These findings highlight the central role of betaKlotho in bile acid homeostasis and raise the possibility that this protein could be a pharmacologic target for the treatment of gallstones... - MicroRNA let-7 regulates 3T3-L1 adipogenesisTingwan Sun
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390 9050, USA
Mol Endocrinol 23:925-31. 2009..These results suggest that let-7 plays an important role in adipocyte differentiation and that it does so in part by targeting HMGA2, thereby regulating the transition from clonal expansion to terminal differentiation... - Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodesZhu Wang
Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Proc Natl Acad Sci U S A 106:9138-43. 2009..stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes... - Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary aminesJon L Collins
J Med Chem 45:1963-6. 2002..12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism... - Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestineInsook Kim
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
J Lipid Res 48:2664-72. 2007..These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1... - Enhanced acetaminophen toxicity by activation of the pregnane X receptorGrace L Guo
Laboratory of Metabolism, CCR, NCI, NIH, Bethesda, Maryland 20892, USA
Toxicol Sci 82:374-80. 2004..Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation... - 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforinRyan E Watkins
Department of Chemistry, The University of North Carolina at Chapel Hill, North Carolina 27599, USA
Biochemistry 42:1430-8. 2003.... - Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1Yong Li
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
Mol Cell 17:491-502. 2005..These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and endocrine development and function... - Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic developmentPeili Gu
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Mol Cell Biol 25:3492-505. 2005.... - Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partnerYong Li
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
Proc Natl Acad Sci U S A 102:9505-10. 2005..These results establish a structural model for understanding how SHP interacts with LRH-1 to regulate cholesterol homeostasis and provide new insights into how nuclear receptor/coregulator selectivity is achieved... - The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerizationKelly Suino
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
Mol Cell 16:893-905. 2004..These structural observations provide a molecular framework for understanding the atypical transcriptional activation properties of CAR... - Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicityGrace L Guo
Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA
J Biol Chem 278:45062-71. 2003..Furthermore, FXR, PXR, and CAR protect against hepatic bile acid toxicity in a complementary manner, suggesting that they serve as redundant but distinct layers of defense to prevent overt hepatic damage by bile acids during cholestasis... - International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptorDavid D Moore
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Pharmacol Rev 58:742-59. 2006..This review summarizes results of structural, pharmacologic, and genetic studies of these receptors... - Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cellsDeborah M Muoio
Department of Medicine and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
Diabetes 51:901-9. 2002..These results demonstrate a role for hPPAR-alpha in regulating muscle lipid homeostasis... - Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicinJill E Chrencik
Department of Chemistry, Campus Box 3290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
Mol Endocrinol 19:1125-34. 2005..These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics... - Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognitionYu Xue
Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 3290, USA
Mol Endocrinol 21:1028-38. 2007..The results provide detailed insights into the manner in which human PXR responds to a wide range of endobiotic compounds...
Research Grants
- Protection of Intestine by the Bile Acid Receptor FXRSteven Kliewer; Fiscal Year: 2007..abstract_text> ..
- Bile Acid and Estrogen Receptors in Colon CancerSteven Kliewer; Fiscal Year: 2009..Moreover, since both FXR and ERbeta can be regulated by small molecule ligands, these studies may reveal novel opportunities for treating and preventing colon cancer. ..
- Regulation of Metabolism by the Hormone FGF15/19Steven A Kliewer; Fiscal Year: 2010..Insights from these studies may provide new clinical strategies for treating obesity, diabetes, and other forms of metabolic disease. ..
- Bile Acid and Estrogen Receptors in Colon CancerSteven Kliewer; Fiscal Year: 2007..Moreover, since both FXR and ERbeta can be regulated by small molecule ligands, these studies may reveal novel opportunities for treating and preventing colon cancer. ..