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Last year’s Award Winner Daniel Merk and a team at Goethe University Frankfurt discovered another nuclear receptor as responsive to thyroid hormones.
Thyroid hormones crucially regulate numerous physiological functions through activation of the two nuclear thyroid hormone receptors (THR) that act as ligand-sensing transcription factors. A team at the Institute of Pharmaceutical Chemistry of Goethe University Frankfurt has discovered another nuclear receptor as responsive to thyroid hormones. L-Thyroxin and its metabolite 3,3′,5,5′-tetraiodothyroacetic acid (TETRAC) were found to robustly activate the peroxisome proliferator-activated receptor gamma (PPARγ).
The co-crystal structure of PPARγ in complex with TETRAC revealed the endogenous ligand differing in its binding mode from typical PPARγ agonists such as the antidiabetic drug rosiglitazone by forming no direct contact with the canonical activation function of the nuclear receptor suggesting weaker activation efficacy. However, TETRAC also turned out as agonist of PPAR’s heterodimer partner retinoid X receptor and activated the PPARγ:RXR heterodimer with stronger efficacy than rosiglitazone.
In native cellular settings, TETRAC promoted PPARγ regulated gene expression and this activity was not compromised by knockdown of the THRs demonstrating that the thyroid hormone modulates PPAR signaling in a THR independent pathway. Administration of brominated analogues of L-thyroxin and TETRAC to mice caused enhanced PPARγ regulated gene expression, too, but revealed a delayed effect of the L-thyroxin analogue suggesting that metabolic conversion to the TETRAC analogue was required.
These findings suggest interestingly that direct modulation of PPARγ involves in thyroid hormone signaling. Therein, differential metabolic activation of L-thyroxin – to 3,3′,5-triiodo-L-thyronine or to TETRAC – might be an important switch between THR and PPARγ mediated activities of thyroid hormones. Additionally, TETRAC evolves as potent endogenous ligand for the putative fatty acid sensor PPARγ with potential physiological relevance.
The full article can be found at: https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b02150
The authors around Daniel Merk are grateful to the Aventis Foundation for the Life Sciences Bridge Award which has importantly contributed to the success of this project.