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The Regulation of Glucocorticoid and Mineralocorticoid Hormone Action by 11beta-Hydroxysteroid Dehydrogenases

English title The Regulation of Glucocorticoid and Mineralocorticoid Hormone Action by 11beta-Hydroxysteroid Dehydrogenases
Applicant Odermatt Alexander
Number 124912
Funding scheme Project funding
Research institution Universität Basel
Institution of higher education University of Basel - BS
Main discipline Biochemistry
Start/End 01.05.2009 - 30.04.2012
Approved amount 473'665.00
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Keywords (13)

steroid metabolism; glucocorticoid receptor; mineralocorticoid recepto; hypertension; diabetes; metabolic syndrome; glucocorticoid receptor; mineralocorticoid receptor; 11beta-hydroxysteroid dehydrogenase; endoplasmic reticulum; NADPH; inflammation; metabolism

Lay Summary (English)

Lead
Lay summary

Glucocorticoids are involved in the regulation of most physiological processes and impaired glucocorticoid action has been associated with several major diseases. The aim of this project was to elucidate molecular mechanisms underlying the control of local glucocorticoid availability and activation of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in different situations. Further, since local glucocorticoid activation depends on cofactor NADPH in the endoplasmic reticulum (ER), we studied mechanisms affecting luminal NADPH availability. Biochemical and cell biological methods were applied. Using 3D-structure modeling and biochemical methods, we attempted to identify inhibitors of 11beta-hydroxysteroid dehydrogenase (11b-HSD) 1 and 2, which convert inactive into active glucocorticoids and the reverse reaction, respectively.

Our results provide evidence for the existence of a hexose-6-phosphate isomerase in the ER of hepatocytes and adipocytes. This isomerase may explain the observed stimulation of NADPH dependent glucocorticoid activation by fructose-6-phosphate and glucose-6-phospate. High fructose diet, by increasing levels of active glucocorticoids, may contribute to metabolic disturbances. Using hepatocyte cell models, we found that glucocorticoids suppress the transcription factor Nrf2, which is involved in cellular defense against oxidative stress. Thus, chronically elevated glucocorticoids may cause impaired defense against oxidative stress. Moreover, we also discovered a new function of 11b-HSD1 in the oxoreduction of the bile acid 7-oxolithocholic acid. Elevated glucocorticoids may thus interfere with bile acid metabolism, which may be relevant for detoxification of oxidized lipids and xenobiotics. Employing a macrophage/microglia cell model, we demonstrated a differential regulation of the NFkB pathway and the control of inflammatory mediators by the GR and MR. We showed that MR antagonists and 11b-HSD1 inhibitors effectively modulated the inflammatory parameters. The balanced action of the two receptors was tightly regulated by 11b-HSD1-dependent glucocorticoid activation. Finally, we identified several glycyrrhetinic acid-derived compounds that selectively inhibited 11b-HSD1 and 2, respectively, that can be used in future in vitro and in vivo studies to modulate glucocorticoid availability.

The results provide a novel link between NADPH generation and utilization in the ER and the control of glucocorticoid formation. The results impact on local activation of GR and MR, which is important in the regulation of metabolism and immune responses. The results are of interest for basic researchers, clinical scientists and drug development specialists.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Suppression of the Nrf2-Dependent Antioxidant Response by Glucocorticoids and 11β-HSD1-Mediated Glucocorticoid Activation in Hepatic Cells.
Kratschmar Denise V, Calabrese Diego, Walsh Jo, Lister Adam, Birk Julia, Appenzeller-Herzog Christian, Moulin Pierre, Goldring Chris E, Odermatt Alex (2012), Suppression of the Nrf2-Dependent Antioxidant Response by Glucocorticoids and 11β-HSD1-Mediated Glucocorticoid Activation in Hepatic Cells., in PloS one, 7(5), 36774-36774.
The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation.
Fürstenberger Cornelia, Vuorinen Anna, Da Cunha Thierry, Kratschmar Denise V, Saugy Martial, Schuster Daniela, Odermatt Alex (2012), The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation., in Toxicological sciences : an official journal of the Society of Toxicology, 126(2), 353-61.
Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases: an overview.
Odermatt Alex, Kratschmar Denise V (2012), Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases: an overview., in Molecular and cellular endocrinology, 350(2), 168-86.
Endocrine disrupting chemicals.
Blumberg Bruce, Iguchi Taisen, Odermatt Alex (2011), Endocrine disrupting chemicals., in The Journal of steroid biochemistry and molecular biology, 127(1-2), 1-3.
Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1.
Odermatt Alex, Da Cunha Thierry, Penno Carlos A, Chandsawangbhuwana Charlie, Reichert Christian, Wolf Armin, Dong Min, Baker Michael E (2011), Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1., in The Biochemical journal, 436(3), 621-9.
Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11β-hydroxysteroid dehydrogenase type 2.
Kratschmar Denise V, Vuorinen Anna, Da Cunha Thierry, Wolber Gerhard, Classen-Houben Dirk, Doblhoff Otto, Schuster Daniela, Odermatt Alex (2011), Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11β-hydroxysteroid dehydrogenase type 2., in The Journal of steroid biochemistry and molecular biology, 125(1-2), 129-42.
Identification of chemically diverse, novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening.
Schuster Daniela, Kowalik Dorota, Kirchmair Johannes, Laggner Christian, Markt Patrick, Aebischer-Gumy Christel, Ströhle Fabian, Möller Gabriele, Wolber Gerhard, Wilckens Thomas, Langer Thierry, Odermatt Alex, Adamski Jerzy (2011), Identification of chemically diverse, novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening., in The Journal of steroid biochemistry and molecular biology, 125(1-2), 148-61.
Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors.
Gaware Rawindra, Khunt Rupesh, Czollner Laszlo, Stanetty Christian, Da Cunha Thierry, Kratschmar Denise V, Odermatt Alex, Kosma Paul, Jordis Ulrich, Classen-Houben Dirk (2011), Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors., in Bioorganic & medicinal chemistry, 19(6), 1866-80.
Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors.
Stanetty Christian, Czollner Laszlo, Koller Iris, Shah Priti, Gaware Rawindra, Cunha Thierry Da, Odermatt Alex, Jordis Ulrich, Kosma Paul, Classen-Houben Dirk (2010), Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors., in Bioorganic & medicinal chemistry, 18(21), 7522-41.
Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum: possible implication in the metabolic syndrome.
Senesi Silvia, Legeza Balázs, Balázs Zoltán, Csala Miklós, Marcolongo Paola, Kereszturi Eva, Szelényi Péter, Egger Christine, Fulceri Rosella, Mandl József, Giunti Roberta, Odermatt Alex, Bánhegyi Gábor, Benedetti Angelo (2010), Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum: possible implication in the metabolic syndrome., in Endocrinology, 151(10), 4830-9.
Steroids: Modulators of inflammation and immunity.
Chapman Karen E, Odermatt Alex (2010), Steroids: Modulators of inflammation and immunity., in The Journal of steroid biochemistry and molecular biology, 120(2-3), 67-8.
The UV-filter benzophenone-1 inhibits 17beta-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals.
Nashev Lyubomir G, Schuster Daniela, Laggner Christian, Sodha Seloni, Langer Thierry, Wolber Gerhard, Odermatt Alex (2010), The UV-filter benzophenone-1 inhibits 17beta-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals., in Biochemical pharmacology, 79(8), 1189-99.
The glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 has broad substrate specificity: Physiological and toxicological considerations.
Odermatt Alex, Nashev Lyubomir G (2010), The glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 has broad substrate specificity: Physiological and toxicological considerations., in The Journal of steroid biochemistry and molecular biology, 119(1-2), 1-13.
11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches.
Rollinger Judith M, Kratschmar Denise V, Schuster Daniela, Pfisterer Petra H, Gumy Christel, Aubry Evelyne M, Brandstötter Sarah, Stuppner Hermann, Wolber Gerhard, Odermatt Alex (2010), 11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches., in Bioorganic & medicinal chemistry, 18(4), 1507-15.
Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases.
Beseda Igor, Czollner Laszlo, Shah Priti S, Khunt Rupesh, Gaware Rawindra, Kosma Paul, Stanetty Christian, Del Ruiz-Ruiz Maria Carmen, Amer Hassan, Mereiter Kurt, Da Cunha Thierry, Odermatt Alex, Classen-Houben Dirk, Jordis Ulrich (2009), Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases., in Bioorganic & medicinal chemistry, 18(1), 433-54.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Congress on Endocrine Disruptors, bioassays for the identification of xenobiotics interfering with steroid modulating enzymes: disruption of key regulators of endocrine functions 14.02.2012 München, Germany
Impact of glucocorticoids on liver function: the need for better in vitro models 10.11.2011 Basel
Dehydrogenases in xenobiotics metabolism and toxicokinetics 29.08.2011 Zürich
Toxikologisches Kolloquim, Modulation of the anti-oxidant response pathway by glucocorticoids 09.08.2011 Basel
Congress on Steroid Research, Coupling of 11b-hydroxysteroid dehydrogenase 1 functions to energy supply and NADPH generation in the ER 28.03.2011 Chicago, USA
Identification of chemicals interfering with steroid metabolism: potential drugs and endocrine disruptors 11.11.2010 Basel
Dehydrogenases in xenobiotics metabolism and toxicokinetics 23.08.2010 Zürich
Mechanisms and in vitro predition of non-allergic idiosyncratic toxicity 19.11.2009 Geneva
The role of dehydrogenases in xenobiotic metabolism 07.09.2009 Zürich
Keeping the balance of glucocorticoid action by modulators of 11b-hydroxysteroid dehydrogenase - from basic science to therapy 02.09.2009 Bern
Adjusting the balance of corticosteroid hormone action: nutritional strategy to prevent metabolic disorders 21.07.2009 Kaiseraugst
Control of glucocorticoid balance by 11beta-hydroxysteroid dehydrogenases 22.06.2009 Innsbruck, Austria
ASPEX Meeting Inhibitors of 11beta-hydroxysteroid dehydrogenases 07.05.2009 Wien, Austria


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Reproductive Toxicology: Male Fertility 26.03.2012 Bern
Endocrine Modulators 05.03.2012 Bern


Communication with the public

Communication Title Media Place Year
Print (books, brochures, leaflets) In house: biozentrum/pharmazentrum; Molekular und Systemtoxikologie German-speaking Switzerland 04.04.2012

Associated projects

Number Title Start Funding scheme
133859 Purchase of a laser scanning microscope / LSM710 Carl Zeiss 01.12.2010 R'EQUIP
66575 Disruption of Glucocorticoid- and Mineralocorticoid Receptor-Mediated Responses by Environmental Chemicals 01.01.2002 NRP 50 Endocrine Disruptors
112279 The regulation of glucocorticoid and mineralocorticoid hormone action by 11beta-hydroxysteroid dehydrogenases 01.05.2006 Project funding
140961 Generation and Utilization of NADPH in the Endoplasmic Reticulum: Impact on Metabolic and Hormonal Regulation 01.05.2012 Project funding
121829 Effects of UV filters in aquatic organisms on endocrine fuction and on gene expression using microarrays 01.02.2009 Project funding

Abstract

Purpose and aim of the projectGlucocorticoids and mineralocorticoids are involved in regulating multiple physiological functions including energy metabolism, blood pressure, brain function, immune responses and growth. Most effects of these hormones are mediated by glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). The activation of these receptors is controlled by the pre-receptor enzymes 11beta-hydroxysteroid dehydrogenase (11b-HSD) 1 and 2 that regulate the access of active hormones to the receptors. An impaired function of these receptors and pre-receptor enzymes has been associated with several major diseases such as obesity and type 2 diabetes, hypertension, atherosclerosis, heart failure, osteoporosis, cataract, mood disorders and cancer. Thus, there is a great interest to develop therapeutic strategies to modulate the function of these proteins. Based on our previous findings and preliminary results, we hypothesize a direct coupling of the cellular energy state and glucocorticoid activation in cells expressing 11b-HSD1. After demonstrating that hexose-6-phosphate dehydrogenase (H6PDH) strongly stimulates 11b-HSD1 reductase activity and that extracellular glucose influences 11b-HSD1 activity, we aim at elucidating the impact of intracellular glucose-6-phosphate (G6P) and the role of G6P-transporter (G6PT) and glucose-6-phosphatase (G6Pase) on local glucocorticoid activation. We also aim at uncovering the factors involved in the control of the coupling between energy state and glucocorticoid regeneration and study the impact of the G6PT/G6Pase/H6PDH/11b-HSD1 system on the differentiation of adipocytes and myocytes. Furthermore, we aim at elucidating the influence of cellular stresses (redox changes, reactive oxygen species (ROS), ATP depletion, unfolded protein response, presence of pro-inflammatory cytokines) on the function of 11b-HSDs and on MR and GR activation in different cell types. In previous studies, we addressed aspects important for the safety assessment of 11b-HSD1 inhibitors, including species-specific functions and assessment of compound selectivity. Here, we aim at extending these approaches by studying potential effects of 11b-HSD1 inhibitors on the hepatic metabolism of xenobiotics and by considering structural aspects, ligand set similarity and biological similarity to assess compound specificity. To address physiologically and pharmacologically relevant questions related to MR and GR function and their control by 11b-HSD enzymes, I propose to:I.investigate the molecular mechanisms underlying the coupling of cellular energy state and local glucocorticoid activation by 11b-HSD1;II.elucidate the impact of altered ER luminal glucose-6-phosphate, NADPH and active glucocorticoids on the differentiation of skeletal muscle cells and adipocytes;III.study the effects of ATP depletion and AMP-kinase activation on the regulation of the G6PT/G6Pase/H6PDH/11b-HSD1 system; IV.assess the impact of altered hepatic GR activation and 11b-HSD1 function on the regulation of xenobiotics metabolism; V.elucidate the molecular mechanisms underlying MR activation by 11b-HSDs; VI.study the selectivity of steroid mimetics by considering structural aspects, intracellular compartmentalization and ligand set similarity. To achieve our goal, we will use siRNA, shRNA and overexpression vectors to assess effects on enzyme and receptor function and to study their impact on cell differentiation in transiently and stably transfected cells. In addition, we aim at establishing stem cell-based systems to study effects on cell differentiation. We will establish the use of Array Scan technology for high-content analysis, which facilitates measurements of nuclear receptor activation and metabolic parameters in assessing effects of cellular stress on hormone-mediated regulation. The planned animal experiments will be carried out together with our collaborators. Furthermore, we plan to establish LC-MS/MS-based detection of steroid hormone metabolites, extending the possibilities to exploit analyses from animal experiments. In collaborative projects, we will continue to apply structure-based methods to study ligand target interactions. The proposed research is relevant for uncovering basic mechanisms of glucocorticoid and mineralocorticoid action in health and disease states as well as for general understanding of steroid hormone action and pre-receptor regulation. Specifically, the knowledge gained from the proposed research may support the development of therapeutic interventions targeting MR and GR as well as 11b-HSDs to control corticosteroid hormone action.
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