l -Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ
| Autor: | Iris Bischoff, Julius Pollinger, Silvia Arifi, Jan Heering, Whitney Kilu, Manfred Schubert-Zsilavecz, Robert Fürst, Pascal Heitel, Mario Wurglics, Dieter Steinhilber, Werner Pogoda, Stefan Knapp, Leonie Gellrich, Ewgenij Proschak, Alexander Paulke, Apirat Chaikuad, Tamara Goebel, Astrid S. Kahnt, Daniel Merk |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Models Molecular Protein Conformation Drug Evaluation Preclinical Peroxisome proliferator-activated receptor Retinoid X receptor 01 natural sciences Mice 03 medical and health sciences Drug Discovery medicine Animals Amino Acid Sequence Receptor 030304 developmental biology chemistry.chemical_classification 0303 health sciences Thyroid hormone receptor Thyroid Peroxisome Ligand (biochemistry) 0104 chemical sciences Cell biology PPAR gamma Thyroxine 010404 medicinal & biomolecular chemistry medicine.anatomical_structure chemistry Molecular Medicine Hormone |
| Zdroj: | Journal of Medicinal Chemistry. 63:6727-6740 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology. |
| Databáze: | OpenAIRE |
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