steroid metabolism; glucocorticoid receptor; mineralocorticoid recepto; hypertension; diabetes; metabolic syndrome; glucocorticoid receptor; mineralocorticoid receptor; 11beta-hydroxysteroid dehydrogenase; endoplasmic reticulum; NADPH; inflammation; metabolism
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.
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.
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.
Blumberg Bruce, Iguchi Taisen, Odermatt Alex (2011), Endocrine disrupting chemicals., in The Journal of steroid biochemistry and molecular biology
, 127(1-2), 1-3.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.