2. Academic Validation
  3. l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ

l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ

  • J Med Chem. 2020 Jul 9;63(13):6727-6740. doi: 10.1021/acs.jmedchem.9b02150.
Leonie Gellrich 1,  Pascal Heitel 1,  Jan Heering 2,  Whitney Kilu 1,  Julius Pollinger 1,  Tamara Goebel 1,  Astrid Kahnt 1,  Silvia Arifi 1,  Werner Pogoda 3,  Alexander Paulke 3,  Dieter Steinhilber 1 2,  Ewgenij Proschak 1 2,  Mario Wurglics 1,  Manfred Schubert-Zsilavecz 1,  Apirat Chaikuad 1 4,  Stefan Knapp 1 4,  Iris Bischoff 5,  Robert Fürst 5,  Daniel Merk 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
  • 2 Branch for Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany.
  • 3 Department of Forensic Toxicology, Institute of Forensic Medicine, Goethe University Frankfurt, Kennedyallee 104, D-60596 Frankfurt, Germany.
  • 4 Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Max-von-Laue-Straße 15, D-60438 Frankfurt, Germany.
  • 5 Institute of Pharmaceutical Biology, Goethe University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
PMID: 32356658 DOI: 10.1021/acs.jmedchem.9b02150
Abstract

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.

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