Why the MDGL compound MGL-3196 may reduce fibrosis in man, as assessed in rodent models.
MDGL had made a great run on the early PH2 NASH results, but the holy grail is reversal of fibrosis. (In the early days, PNAS was considered a biased journal, based on reviewer selectivity. Not so much if at all any more. I was fortunate to have several pubs in PNAS, thanks to great postdocs and grad students.) I hope a few reading this board took the opportunity to pick up some MDGL shares this summer when I mentioned the opportunity. What a nice run, exciting times. Though this article shows in animals models that TH may block the progression of liver and skin fibrosis, the lipotoxicity hypothesis suggest that there could be reversal of pre-existing fibrosis. Humans are the best model here, using as an example the longer term reversal of fibrosis after resolution of HCV infection in man. That is due to the amazing potential for liver regeneration.
Thyroid hormones inhibit TGF-ß signaling and attenuate fibrotic responses
Proceedings of the National Academy of Sciences
vol. 113 no. 24Elvira Alonso-Merino, E3451–E3460, doi: 10.1073/pnas.1506113113
Elvira Alonso-Merino a, 1, Rosa Martín Orozco a, 1, Lidia Ruíz-Llorente a, Olaia A. Martínez-Iglesias a, Juan Pedro Velasco-Martín b, Ana Montero-Pedrazuela a, Luisa Fanjul-Rodríguez a, Constanza Contreras-Jurado a, Javier Regadera b, and Ana Aranda a, 2 Author Affiliations
Instituto de Investigaciones Biomédicas “Alberto Sols,” Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain;bDepartamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 20829 Madrid, SpainEdited by Michael G. Rosenfeld, University of California, San Diego, La Jolla, CA, and approved May 2, 2016 (received for review March 30, 2015)
Significance
We show here that binding of the thyroid hormone triiodothyronine to the thyroid hormone receptors (TRs) antagonizes TGF-ß/SMAD (mothers against decapentaplegic)-dependent transcription. Transcriptionally inactive TR mutants that do not bind coactivators retained most of the capacity of suppressing transactivation by TGF-ß/SMAD, whereas selective mutations in the DNA binding domain abolished this action. TGF-ß is a major profibrogenic cytokine, and through this transcriptional mechanism, the hormone-bound TRs act as an endogenous barrier to moderate liver and skin fibrosis. These antagonistic actions on TGF-ß/SMAD transcription suggest that TR ligands might be used to block the progression of fibrotic diseases. The natural hormone cannot be used clinically because of severe adverse effects, but novel synthetic ligands with fewer effects might be potentially developed and used.
Abstract
TGF-ß, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-ß/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-ß, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases. |
