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Dive into the research topics where David J. Mangelsdorf is active.

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Featured researches published by David J. Mangelsdorf.


Cell | 1995

The nuclear receptor superfamily: The second decade

David J. Mangelsdorf; Carl S. Thummel; Miguel Beato; Peter Herrlich; Günther Schütz; Kazuhiko Umesono; Bruce Blumberg; Philippe Kastner; Manuel Mark; Pierre Chambon; Ronald M. Evans

David J. Mangelsdorf,’ Carl Thummel,2 Miguel Beato,3 Peter Herrlich,4 Giinther Schiitq5 Kazuhiko Umesono,6 Bruce Blumberg,’ Philippe Kastner,’ Manuel Mark,* Pierre Chambon,8 and Ronald M. Evan&‘* ‘Howard Hughes Medical Institute University of Texas Southwestern Medical Center Dallas, Texas 75235-9050 *Howard Hughes Medical Institute University of Utah Salt Lake City, Utah 84112 31nstutut fiir Molekularbiologie und Tumorforschung 35037 Marburg Federal Republic of Germany 4Forschungszentrum Karlsruhe lnstitut Genetik 76021 Karlsruhe Federal Republic of Germany 5Deutsches Krebsforschungszentrum 69120 Heidelberg Federal Republic of Germany GAdvanced Institute of Science and Technology Graduate School of Biological Sciences Nara 630-01 Japan ‘The Salk Institute for Biological Studies La Jolla, California 92037-5800 Blnstitut de Genetique et de Biologie Moleculaire et Cellulaire Centre National de la Recherche Scientifique lnstitut National de la Sante et de la Recherche M6dicale 67404 lllkirch Cedex Strasbourg France gHoward Hughes Medical Institute The Salk Institute for Biological Studies La Jolla, California 92037-5800


Cell | 1995

The RXR heterodimers and orphan receptors

David J. Mangelsdorf; Ronald M. Evans

The nuclear receptor superfamily is comprised of over 150 different proteins that have evolved to mediate a complex array of extracellular signals into transcriptional responses. Many, but not all, of these proteins directly bind to signaling molecules, which, because of their small lipophilic character, can easily enter the target cell. Thus, unlike membrane-bound receptors, the nuclear receptors are intracellular and function to control the activity of target genes directly. In aggregate, these target genes comprise a genetic network whose coordinate activity defines the physiologic response. The purpose of this review is to establish the historical links between the steroid and nonsteroid receptor signaling systems, to chart the explosive development of the retinoid X receptor (RXR) heterodimer and orphan receptor family, to explain the impact of these discoveries on our understanding of the mechanisms of hormonal signaling, and, finally, to present emerging issues and implications of these studies for animal development, physiology, and human disease.


Cell | 1992

9-cis retinoic acid is a high affinity ligand for the retinoid X receptor

Richard A. Heyman; David J. Mangelsdorf; Jacqueline A. Dyck; Robert B. Stein; Gregor Eichele; Ronald M. Evans; Christina Thaller

All-trans retinoic acid (RA) has previously been shown to modulate the transcriptional properties of the retinoic acid receptor (RAR) and retinoid X receptor (RXR). The inability of all-trans RA to bind to RXR suggests that it may be metabolized to a more active high affinity ligand. We report here an experimental approach that has identified 9-cis RA as an RXR ligand. It is up to 40-fold more potent than all-trans RA in transfection assays and binds with high affinity. The production of 9-cis RA in cultured cells and the identification of this molecule in liver and kidney demonstrates the existence of this molecule in living organisms. The discovery of this novel hormone points to the key role retinoid metabolism may have in generating new signaling pathways.


Cell | 1998

Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα

Daniel J. Peet; Stephen D. Turley; Wenzhen Ma; Bethany A. Janowski; Jean Marc A Lobaccaro; Robert E. Hammer; David J. Mangelsdorf

We demonstrate that mice lacking the oxysterol receptor, LXR alpha, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amount of cholesterol in excess of that which they synthesize de novo. When fed diets containing cholesterol, LXR alpha (-/-) mice fail to induce transcription of the gene encoding cholesterol 7alpha-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is associated with a rapid accumulation of large amounts of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXR alpha (-/-) mice. These results demonstrate the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and establish the role of LXR alpha as the major sensor of dietary cholesterol.


Molecular Cell | 2000

Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors

Timothy T. Lu; Makoto Makishima; Joyce J. Repa; Kristina Schoonjans; Thomas A. Kerr; Johan Auwerx; David J. Mangelsdorf

The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathways rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1). The nuclear receptor LXRalpha binds oxysterols and mediates feed-forward induction. Here, we show that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator, LRH-1; and the promoter-specific repressor, SHP. Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH-1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results reveal an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.


Journal of Clinical Investigation | 2004

Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

Mitsuhiro Watanabe; Sander M. Houten; Li Wang; Antonio Moschetta; David J. Mangelsdorf; Richard A. Heyman; David D. Moore; Johan Auwerx

We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) alpha and beta, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXR alpha and LXR beta. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.


Cell | 2006

Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network

Angie L. Bookout; Yangsik Jeong; Michael Downes; Ruth T. Yu; Ronald M. Evans; David J. Mangelsdorf

In multicellular organisms, the ability to regulate reproduction, development, and nutrient utilization coincided with the evolution of nuclear receptors (NRs), transcription factors that utilize lipophilic ligands to mediate their function. Studying the expression profile of NRs offers a simple, powerful way to obtain highly relational information about their physiologic functions as individual proteins and as a superfamily. We surveyed the expression of all 49 mouse NR mRNAs in 39 tissues, representing diverse anatomical systems. The resulting data set uncovers several NR clades whose patterns of expression indicate their ability to coordinate the transcriptional programs necessary to affect distinct physiologic pathways. Remarkably, this regulatory network divides along the following two physiologic paradigms: (1) reproduction, development, and growth and (2) nutrient uptake, metabolism, and excretion. These data reveal a hierarchical transcriptional circuitry that extends beyond individual tissues to form a meganetwork governing physiology on an organismal scale.


Cell | 1991

A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR

David J. Mangelsdorf; Kazuhiko Umesono; Steven A. Kliewer; Uwe K. Borgmeyer; Estelita S. Ong; Ronald M. Evans

The vitamin A derivative retinoic acid exerts its effects on transcription through two distinct classes of nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). We provide evidence that expression of the gene for cellular retinol-binding protein type II (CRBPII), a key protein in the intestinal absorption of vitamin A, is dramatically up-regulated by retinoic acid in the presence of RXR but not RAR. This regulation is conferred through a specific cis element in the CRBPII promoter that contains five nearly perfect tandem repeats of the sequence AGGTCA spaced by a single nucleotide. The discovery of this new RX response element provides a means for distinguishing between the two retinoid receptor systems and suggests that an RXR-mediated pathway exists for modulating vitamin A metabolism.


Proceedings of the National Academy of Sciences of the United States of America | 2003

Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue

Bryan A. Laffitte; Lily C. Chao; Jing Li; Robert Walczak; Sarah Hummasti; Sean B. Joseph; Antonio Castrillo; Damien C. Wilpitz; David J. Mangelsdorf; Jon L. Collins; Enrique Saez; Peter Tontonoz

The control of lipid and glucose metabolism is closely linked. The nuclear receptors liver X receptor (LXR)α and LXRβ have been implicated in gene expression linked to lipid homeostasis; however, their role in glucose metabolism is not clear. We demonstrate here that the synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Analysis of gene expression in LXR agonist-treated mice reveals coordinate regulation of genes involved in glucose metabolism in liver and adipose tissue. In the liver, activation of LXR led to the suppression of the gluconeogenic program including down-regulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase expression. Inhibition of gluconeogenic genes was accompanied by an induction in expression of glucokinase, which promotes hepatic glucose utilization. In adipose tissue, activation of LXR led to the transcriptional induction of the insulin-sensitive glucose transporter, GLUT4. We show that the GLUT4 promoter is a direct transcriptional target for the LXR/retinoid X receptor heterodimer and that the ability of LXR ligands to induce GLUT4 expression is abolished in LXR null cells and animals. Consistent with their effects on GLUT4 expression, LXR agonists promote glucose uptake in 3T3-L1 adipocytes in vitro. Thus, activation of LXR alters the expression of genes in liver and adipose tissue that collectively would be expected to limit hepatic glucose output and improve peripheral glucose uptake. These results outline a role for LXRs in the coordination of lipid and glucose metabolism.


Cell | 1990

Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene

Roland Schüle; Kazuhiko Umesono; David J. Mangelsdorf; Jack Bolado; J. Wesley Pike; Ronald M. Evans

We present evidence that the vitamin D response element in the human osteocalcin gene confers responsiveness to the vitamin A metabolite, retinoic acid. Retinoic acid receptor (RAR) expressed in E. coli binds to this sequence in vitro. Transfection of RAR expression vectors in cultured cells activates heterologous promoters containing this sequence in vivo. This response element contains a consensus AP-1 site TGACTCA and in vitro is bound by the Jun-Fos complex. Unexpectedly, cotransfection of Jun and Fos expression vectors suppresses basal level transcription of the osteocalcin gene and suppresses induction by both retinoic acid and vitamin D3. Additional studies delimit an 11 nucleotide segment as a minimal hormone response element containing the AP-1 site as its core. These results indicate that two distinct classes of transcription factors can recognize common regulatory sequences, a phenomenon we refer to as cross-coupling.

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Steven A. Kliewer

University of Texas Southwestern Medical Center

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Angie L. Bookout

University of Texas Southwestern Medical Center

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Joyce J. Repa

University of Texas Southwestern Medical Center

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John D. Minna

University of Texas Southwestern Medical Center

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Yuan Zhang

University of Texas Southwestern Medical Center

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Luc Girard

University of Texas Southwestern Medical Center

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