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Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses
Open accessAbstract
TGF-β, 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-β/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-β, 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.
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“Thyroid hormones reduce hepatic steatosis by stimulating hepatic lipophagy and mitochondrial biogenesis, and by inhibiting hepatic lipogenesis.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [348]
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“They can also interfere with fi brogenesis by inhibiting TGFb signalling.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [348]
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1 retracted
Bagnato, G., Bitto, A., Irrera, N., Pizzino, G., Sangari, D., Cinquegrani, M., Roberts, W. N., Atteritano, M., Altavilla, D., Squadrito, F., et al. (2013) · Arthritis Research & Therapy · doi:10.1186/ar4300 · Cited by 19
RetractedBataller, R., & Brenner, D. A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24282 · Cited by 4,958
Massagué, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3434 · Cited by 3,239
Smad transcription factorsPreprint
Massagué, J., Seoane, J., & Wotton, D. (2005) · Genes & Development · doi:10.1101/gad.1350705 · Cited by 2,519
Thyroid Hormone Regulation of Metabolism
Mullur, R., Liu, Y.-Y., & Brent, G. A. (2014) · Physiological Reviews · doi:10.1152/physrev.00030.2013 · Cited by 2,421
TLR4 enhances TGF-β signaling and hepatic fibrosis
Seki, E., De Minicis, S., Österreicher, C. H., Kluwe, J., Osawa, Y., Brenner, D. A., & Schwabe, R. F. (2007) · Nature Medicine · doi:10.1038/nm1663 · Cited by 1,942
SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS
Feng, X.-H., & Derynck, R. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.022404.142018 · Cited by 1,869
Pathogenesis of Liver Fibrosis
Hernandez-Gea, V., & Friedman, S. L. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130246 · Cited by 1,809
TGFβ signals through a heteromeric protein kinase receptor complex
Wrana, J. L., Attisano, L., Cárcamo, J. M., Zentella‐Dehesa, A., Doody, J. F., Laiho, M., Wang, X.-F., & Massagué, J. (1992) · Cell · doi:10.1016/0092-8674(92)90395-s · Cited by 1,528
Liver fibrosis and repair: Immune regulation of wound healing in a solid organ
Pellicoro, A., Ramachandran, P., Iredale, J. P., & Fallowfield, J. A. (2014) · Nature Reviews Immunology · doi:10.1038/nri3623 · Cited by 1,310
Mechanisms of thyroid hormone action
Brent, G. A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60047 · Cited by 1,244
Smad7 Binds to Smurf2 to Form an E3 Ubiquitin Ligase that Targets the TGFβ Receptor for Degradation
Kavsak, P., Rasmussen, R. K., Causing, C. G., Bonni, S., Zhu, H., Thomsen, G. H., & Wrana, J. L. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00134-9 · Cited by 1,205
TGF-β in progression of liver disease
Dooley, S., & ten Dijke, P. (2012) · Cell and Tissue Research · doi:10.1007/s00441-011-1246-y · Cited by 718
A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response
Ding, N., Yu, R. T., Subramaniam, N., Sherman, M. H., Wilson, C., Rao, R., Leblanc, M., Coulter, S., He, M., Scott, C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.028 · Cited by 622
Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling
Mullen, A. C., Orlando, D. A., Newman, J. J., Lovén, J., Kumar, R., Bilodeau, S., Reddy, J., Guenther, M. G., DeKoter, R. P., & Young, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.08.050 · Cited by 580
Structural determinants of nuclear receptor assembly on DNA direct repeats
Rastinejad, F., Perlmann, T., Evans, R. M., & Sigler, P. B. (1995) · Nature · doi:10.1038/375203a0 · Cited by 578
PPM1A Functions as a Smad Phosphatase to Terminate TGFβ Signaling
Lin, X., Duan, X., Liang, Y.-Y., Su, Y., Wrighton, K. H., Long, J., Hu, M., Davis, C. M., Wang, J., Brunicardi, F. C., et al. (2006) · Cell · doi:10.1016/j.cell.2006.03.044 · Cited by 486
Emerging insights into Transforming growth factor Smad signal in hepatic fibrogenesis
Inagaki, Y., & Okazaki, I. (2007) · Gut · doi:10.1136/gut.2005.088690 · Cited by 466
Yamamoto, T., Takagawa, S., Katayama, I., Yamazaki, K., Hamazaki, Y., Shinkai, H., & Nishioka, K. (1999) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.1999.00528.x · Cited by 451
Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15Ink4B transcription in response to TGF‐β
Feng, X., Lin, X., & Derynck, R. (2000) · The EMBO Journal · doi:10.1093/emboj/19.19.5178 · Cited by 404
Role of Smads in TGFβ signaling
Heldin, C., & Moustakas, A. (2011) · Cell and Tissue Research · doi:10.1007/s00441-011-1190-x · Cited by 335
Non-alcoholic fatty liver disease across the spectrum of hypothyroidism
Chung, G. E., Kim, D., Kim, W. K., Yim, J. Y., Park, M. J., Kim, Y. J., Yoon, J., & Lee, H.-S. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.02.027 · Cited by 304
Clouthier, D. E., Comerford, S. A., & Hammer, R. E. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119815 · Cited by 282
The Role of Smad3 in Mediating Mouse Hepatic Stellate Cell Activation
Schnabl, B., Kweon, Y. O., Frederick, J. P., Wang, X.-F., Rippe, R. A., & Brenner, D. A. (2001) · Hepatology · doi:10.1053/jhep.2001.25349 · Cited by 256
Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism
Sinha, R. A., Singh, B. K., & Yen, P. M. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.07.001 · Cited by 253
Narrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel Therapies
Rosenbloom, J., Castro, S. V., & Jimenez, S. A. (2010) · Annals of Internal Medicine · doi:10.7326/0003-4819-152-3-201002020-00007 · Cited by 230
Targeted Disruption of TGF-β/Smad3 Signaling Modulates Skin Fibrosis in a Mouse Model of Scleroderma
Lakos, G., Takagawa, S., Chen, S.-J., Ferreira, A. M., Han, G., Masuda, K., Wang, X., DiPietro, L. A., & Varga, J. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63289-0 · Cited by 216
Thyroid hormone receptors, cell growth and differentiation
Pascual, A., & Aranda, A. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.03.012 · Cited by 213
TGF-β/Smad Signaling in the Injured Liver
Breitkopf, K., Godoy, P., Ciuclan, L. I., Singer, M. V., & Dooley, S. (2006) · Zeitschrift für Gastroenterologie · doi:10.1055/s-2005-858989 · Cited by 176
von Gersdorff, G., Suszták, K., Rezvani, F., Bitzer, M., Liang, D., & Böttinger, E. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.15.11320 · Cited by 169
Yoshida, K., Matsuzaki, K., Mori, S., Tahashi, Y., Yamagata, H., Furukawa, F., Seki, T., Nishizawa, M., Fujisawa, J., & Okazaki, K. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62324-3 · Cited by 165
Thyroid hormone-related regulation of gene expression in human fatty liver.
Pihlajamäki, J., Boes, T., Kim, E.-Y., Dearie, F., Kim, B. W., Schroeder, J., Mun, E., Nasser, I., Park, P. J., Bianco, A. C., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0212 · Cited by 164
Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription
Ross, S., Cheung, E. C. W., Petrakis, T. G., Howell, M. T., Kraus, W. L., & Hill, C. S. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601332 · Cited by 163
Thyroid hormone (T3) and TRβ agonist GC‐1 inhibit/reverse nonalcoholic fatty liver in rats
Perra, A., Simbula, G., Simbula, M., Pibiri, M., Kowalik, M. A., Sulas, P., Cocco, M. T., Ledda‐Columbano, G. M., & Columbano, A. (2008) · The FASEB Journal · doi:10.1096/fj.08-108464 · Cited by 147
Thyroid Hormone Receptor β1 Acts as a Potent Suppressor of Tumor Invasiveness and Metastasis
Martínez-Iglesias, O. A., Garcı́a-Silva, S., Tenbaum, S. P., Regadera, J., Larcher, F., Paramio, J. M., Vennström, B., & Aranda, A. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2198 · Cited by 145
A nonclassical vitamin D receptor pathway suppresses renal fibrosis
Ito, I., Waku, T., Aoki, M., Abe, R., Nagai, Y., Watanabe, T., Nakajima, Y., Ohkido, I., Yokoyama, K., Miyachi, H., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67804 · Cited by 138
Analysis of Smad nucleocytoplasmic shuttling in living cells
Nicolás, F. J., Bosscher, K. D., Schmierer, B., & Hill, C. S. (2004) · Journal of Cell Science · doi:10.1242/jcs.01289 · Cited by 138
Yoshida, K., & Matsuzaki, K. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00053 · Cited by 131
Weng, H., Liu, Y., Chen, J., Huang, T., Xu, L., Godoy, P., Hu, J.-H., Zhou, C., Stickel, F., Marx, A., et al. (2009) · Hepatology · doi:10.1002/hep.22934 · Cited by 131
Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo
Shibusawa, N., Hashimoto, K., Nikrodhanond, A. A., Liberman, M. C., Applebury, M., Liao, X. H., Robbins, J. T., Refetoff, S., Cohen, R., & Wondisford, F. E. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18377 · Cited by 126
Takagawa, S., Lakos, G., Mori, Y., Varga, J., Yamamoto, T., & Nishioka, K. (2003) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.2003.12308.x · Cited by 122
Zhu, X., Hanover, J. A., Hager, G. L., & Cheng, S.-Y. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.42.27058 · Cited by 117
Yamamoto, T., Takagawa, S., Katayama, I., & Nishioka, K. (1999) · Clinical Immunology · doi:10.1006/clim.1999.4720 · Cited by 116
Both Hypothyroidism and Hyperthyroidism Increase Atrial Fibrillation Inducibility in Rats
Zhang, Y., Dedkov, E. I., Teplitsky, D., Weltman, N. Y., Pol, C. J., Rajagopalan, V., Lee, B., & Gerdes, A. M. (2013) · Circulation Arrhythmia and Electrophysiology · doi:10.1161/circep.113.000502 · Cited by 104
Silveira, M. G., Mendes, F. D., Diehl, N. N., Enders, F., & Lindor, K. D. (2009) · Liver International · doi:10.1111/j.1478-3231.2009.02003.x · Cited by 103
Smad3 mediates immediate early induction of Id1 by TGF-β
Liang, Y.-Y., Brunicardi, F. C., & Lin, X. (2008) · Cell Research · doi:10.1038/cr.2008.321 · Cited by 81
The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation
Contreras‐Jurado, C., García-Serrano, L., Gómez-Ferrería, M., Costa, C., Paramio, J. M., & Aranda, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.218487 · Cited by 72
The thyroid hormone receptor β induces DNA damage and premature senescence
Zambrano, A., García-Carpizo, V., Gallardo, M. E., Villamuera, R., Gómez-Ferrerı́a, M. A., Pascual, A., Buisine, N., Sachs, L. M., Garesse, R., & Aranda, A. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201305084 · Cited by 70
Perra, A., Kowalik, M. A., Pibiri, M., Ledda‐Columbano, G. M., & Columbano, A. (2008) · Hepatology · doi:10.1002/hep.22750 · Cited by 61
Thyroid hormone induces myocardial matrix degradation by activating matrix metalloproteinase-1
Roy, S. G., Mishra, S., Ghosh, G., & Bandyopadhyay, A. (2006) · Matrix Biology · doi:10.1016/j.matbio.2006.12.005 · Cited by 59
Pituitary and Plasma Thyrotropin, Thyroxine, and Triiodothyronine after Hyperthyroidism
Obregón, M.-J., Pascual, A., de Escobar, G. M., & del Rey, F. E. (1979) · Endocrinology · doi:10.1210/endo-104-5-1467 · Cited by 57
Pritchard, M. T., Cohen, J. I., Roychowdhury, S., Pratt, B. T., & Nagy, L. E. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.04.017 · Cited by 54
Bruck, R., Oren, R., Shirin, H., Aeed, H., Papa, M. Z., Matas, Z., Zaidel, L., Avni, Y., & Halpern, Z. (1998) · Hepatology · doi:10.1002/hep.510270417 · Cited by 45
López-Fontal, R., Zeini, M., Través, P. G., Gómez-Ferrería, M., Aranda, A., Sáez, G. T., Cerdá, C., Martín‐Sanz, P., Hortelano, S., & Boscá, L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008710 · Cited by 39
Thyroid hormone ameliorates diabetic nephropathy in a mouse model of type II diabetes
Lin, Y., & Sun, Z. (2011) · Journal of Endocrinology · doi:10.1530/joe-10-0340 · Cited by 34
Receptors of thyroid hormones.
Aranda, A., Alonso-Merino, E., & Zambrano, A. (2013) · PubMed · Cited by 28
Garcı́a-Silva, S., Martínez-Iglesias, O. A., Ruiz-Llorente, L., & Aranda, A. (2010) · Oncogene · doi:10.1038/onc.2010.464 · Cited by 27
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Metadata
- Authors
- Alonso-Merino, E., Martín Orozco, R., Ruíz-Llorente, L., Martínez-Iglesias, O. A., Velasco-Martín, J. P., Montero-Pedrazuela, A., Fanjul-Rodríguez, L., Contreras-Jurado, C., Regadera, J., & Aranda, A.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Instituto de Investigaciones Biomédicas “Alberto Sols,” Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain;
- Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 20829 Madrid, Spain
- Universidad Autónoma de Madrid (ES)
- Corresponding author
- Aranda, Ana
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-05-31
- Volume
- 113
- Issue
- 24
- Pages
- E3451-60
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4914168
- OpenAlex
- W2409493994
- Cited by
- 108
- References
- 57
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 21 · 2023: 10 · 2022: 9 · 2021: 11 · 2020: 10 · 2019: 13 · 2018: 6 · 2017: 4 · 2016: 3
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Tesis Doctorals en Xarxa (Consorci de Serveis Universitaris de Catalunya) (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Hispana (submittedVersion, other-oa)
- Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, public-domain)
- Funders
- Ministerio de Economía y Competitividad (BFU2011-28058, BFU2014-53610P)
- Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (RD12/0036/0030)
- Comunidad de Madrid (S2011/BMD-2328)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- thyroid hormones, triiodothyronine, TGF-beta signaling, Smad3, SMAD4, thyroid hormone receptor, transcriptional crosstalk, Smad phosphorylation, Smad binding element, histone acetylation, liver fibrosis, carbon tetrachloride, skin fibrosis, bleomycin, collagen deposition, fibrosis
- MeSH terms
- Animals, Bleomycin, Carbon Tetrachloride Poisoning, Liver Cirrhosis, Triiodothyronine, Signal Transduction, Transforming Growth Factor beta, Mice, Knockout, Mice, Smad3 Protein, Smad4 Protein
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