11beta-hydroxysteroid dehydrogenase; glucose-6-phosphate; redox; oxysterol; macrophage; endoplasmic reticulum; glucocorticoid; bile acid; hexose-6-phosphate dehydrogenase; NADPH
Marbet Philippe, Klusonova Petra, Birk Julia, Kratschmar Denise V., Odermatt Alex (2018), Absence of hexose‐6‐phosphate dehydrogenase results in reduced overall glucose consumption but does not prevent 11β‐hydroxysteroid dehydrogenase‐1‐dependent glucocorticoid activation, in
The FEBS Journal, 285(21), 3993-4004.
Engeli R. T. Fürstenberger C. Kratschmar D. V. and Odermatt A. (2018), Currently available murine Leydig cell lines can be applied to study early steps of steroidogenesis but not testosterone synthesis., in
Heliyon, 4, e00527.
Tsachaki M. Mladenovic N. Stambergova H. Birk J. and Odermatt A. (2018), Hexose-6-phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded protein response, calcium homeostasis and redox balance., in
FASEB J, 32, 2690-2705.
Engeli Roger T., Tsachaki Maria, Hassan Heba A., Sager Christoph P., Essawi Mona L., Gad Yehia Z., Kamel Alaa K., Mazen Inas, Odermatt Alex (2017), Biochemical Analysis of Four Missense Mutations in the HSD17B3 Gene Associated With 46,XY Disorders of Sex Development in Egyptian Patients, in
Journal of Sexual Medicine, 14(9), 1165-1174.
Araya Selene, Kratschmar Denise V., Tsachaki Maria, Stücheli Simon, Beck Katharina R., Odermatt Alex (2017), DHRS7 (SDR34C1) – A new player in the regulation of androgen receptor function by inactivation of 5α-dihydrotestosterone?, in
Journal of Steroid Biochemistry and Molecular Biology, 171, 288-295.
Beck Katharina R., Kaserer Teresa, Schuster Daniela, Odermatt Alex (2017), Virtual screening applications in short-chain dehydrogenase/reductase research, in
Journal of Steroid Biochemistry and Molecular Biology, 171, 157-177.
Legeza Balázs, Marcolongo Paola, Gamberucci Alessandra, Varga Viola, Bánhegyi Gábor, Benedetti Angiolo, Odermatt Alex (2017), Fructose, glucocorticoids and adipose tissue: Implications for the metabolic syndrome, in
Nutrients, 9(5), 426.
Vuorinen Anna, Engeli Roger T., Leugger Susanne, Bachmann Fabio, Akram Muhammad, Atanasov Atanas G., Waltenberger Birgit, Temml Veronika, Stuppner Hermann, Krenn Liselotte, Ateba Sylvin B., Njamen Dieudonné, Davis Rohan A., Odermatt Alex, Schuster Daniela (2017), Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2, in
Journal of Natural Products, 80(4), 965-974.
Beck Katharina R., Bächler Murielle, Vuorinen Anna, Wagner Sandra, Akram Muhammad, Griesser Ulrich, Temml Veronika, Klusonova Petra, Yamaguchi Hideaki, Schuster Daniela, Odermatt Alex (2017), Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole, in
Biochemical Pharmacology, 130, 93-103.
Tsachaki Maria, Meyer Arne, Weger Benjamin, Tokarz Janina, Adamski Jerzy, Belting Heinz-Georg, Affolter Markus, Dickmeis Thomas, Odermatt Alex (2017), Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish, in
Journal of Endocrinology, 232, 323-335.
Morgan R A, Beck K R, Nixon M, Homer N Z M, Crawford A A, Melchers D, Houtman R, Meijer O C, Stomby A, Anderson A J, Upreti R H, Olsson T, Michoel T, Cohain A, Ruusalepp A, Schadt E E, Björkegren J L M, Andrew R, Kenyon C J, Hadoke P W F, Odermatt A, Keen J A, Walker B R (2017), Carbonyl reductase 1 catalyzes 20beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity, in
Scientific Reports, 7, 10633.
Boudon S M, Vuorinen A, Geotti-Bianchini P, Wandeler E, Kratschmar D V, Heidl M, Campiche R, Jackson E, Odermatt A (2017), Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV, in
Plos One, 12, e0171079.
Vuorinen Anna, Engeli Roger T., Leugger Susanne, Kreutz Christoph R., Schuster Daniela, Odermatt Alex, Matuszczak Barbara (2016), Phenylbenzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis, in
Bioorganic and Medicinal Chemistry Letters, 27(13), 2982-2985.
Engeli RT Ben Rhouma B Sager CP Tsachaki M Birk J Fakhfakh F Keskes L Belguith N Odermatt A (2016), Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with 46, XY disorders of sex development, in
J. Steroid Biochem. Mol. Biol., 155, 147-154.
Odermatt A. Strajhar P. Engeli R. T (2016), Disruption of steroidogenesis: cell models for mechanistic investigations and as screening tools, in
J Steroid Biochem Mol Biol, 158, 9-21.
Mani Orlando, Nashev Lyubomir, Livelo Chris, Baker Michael E, Odermatt Alex (2016), Role of Pro-637 and Gln-642 in human glucocorticoid receptors and Ser-843 and Leu-848 in mineralocorticoid receptors in their differential responses to cortisol and aldosterone., in
J Steroid Biochem Mol Biol, 159, 31-40.
Seibert J. K. Quagliata L. Quintavalle C. Hammond T. G. Terracciano L. Odermatt A (2015), A role for the dehydrogenase DHRS7 (SDR34C1) in prostate cancer, in
Cancer Medicine, 4, 1717-1729.
An impaired redox control in the endoplasmic reticulum (ER) with unfolded-protein response (UPR) and ER-stress has been associated with major cardio-metabolic diseases, chronic inflammatory disorders and cancer. Thus, it is crucial to elucidate the mechanisms underlying ER-redox control and identify the affected biological reactions. The NAD(P)+/NAD(P)H redox couple plays an essential role in many biological functions. In contrast to the cytoplasm, the role of the NAD(P)+/NAD(P)H redox couple in the ER and the relevance of luminal NADPH for essential biological functions is insufficiently studied. The discovery of hexose-6-phosphate dehydrogenase (H6PDH) revealed a mechanism for NADPH generation in the ER and provided a link between energy status and glucocorticoid signaling. The glucocorticoid activating 11beta-hydroxysteroid dehydrogenase 1 (11b-HSD1) is, so far, the only well characterized NADPH-dependent luminal enzyme. However, the impact of H6PDH on macrophage function and inflammatory mediators and its effect on corticosteroid signaling remain unknown. Also, there must be other NADPH-dependent enzymes because 11b-HSD1 cannot account for the myopathy and the increased susceptibility of hepatocytes observed in situations of H6PDH-deficiency. Based on previous results, we hypothesize that 1) NADPH-dependent 11b-HSD1 function (glucocorticoid-dependent and -independent) essentially modulates macrophage polarization and activity, and inhibition of 11b-HSD1 exerts anti-inflammatory and anti-infective effects, 2) inhibition of 11b-HSD1 has glucocorticoid-independent metabolic effects by modulating oxysterol and bile acid homeostasis, and 3) ER-luminal short-chain dehydrogenase/reductase (SDR) enzymes other than 11b-HSD1 are responsible for effects in macrophage, adipocytes, adrenal cells, hepatocytes and myocytes in situations of H6PDH-deficiency. Therefore, we propose to investigate the consequences of NADPH depletion in the ER on hormonal and metabolic functions and to characterize enzymatic reactions that are dependent on ER luminal NADPH. Specifically, we propose to:•investigate the role of luminal NADPH supply on macrophage polarization and function. We will distinguish between 11b-HSD1-dependent and -independent effects.•assess a potential role of 11b-HSD1 in the metabolism of EBI-2 ligands•elucidate the impact of luminal NADPH supply and 11b-HSD1 on the metabolism of 7-ketocholesterol (7KC) and on bile acid homeostasis•establish a method using redox-sensitive green-fluorescent proteins (roGFP) to determine the topology of ER membrane proteins in living cells and attempt to identify ER luminal enzymes other than 11b-HSD1•characterize the NADPH-dependence of identified luminal enzymes•develop a strategy to identify novel substrates of SDR enzymesThe role of ER luminal NADPH and the consequences of its depletion on metabolic and hormonal responses will be studied in transfected cells using recombinant enzymes, in cell lines with endogenous expression of the relevant enzymes and treated with siRNA, in primary cells from wild-type and H6PDH knockout mice, and in vivo in wild-type and transgenic mice. Structural modeling will be applied in a search for novel SDR substrates and to further study experimentally verified target-ligand interactions. The proposed research should significantly enhance our current knowledge on the role of NADPH in the ER. The expected findings are relevant regarding the understanding of the coupling between cellular energy state, hormonal regulation, ER redox regulation, and oxidative stress-induced damage. Disturbed functions of the enzymes investigated are associated with impaired inflammatory responses and with cardio-metabolic disorders, and the results of the proposed project should support the future development of therapeutic interventions.