Triiodothyroacetic acid in health and disease

Groeneweg, Stefan; Peeters, Robin P.; Visser, Theo J.; Visser, W. Edward

doi:10.1530/joe-17-0113

Cited by 64 publications

(63 citation statements)

References 189 publications

(282 reference statements)

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“…Diiodothyropropionic acid, a cerebral agonist of T 3 , has also been tested in a few patients, showing some efficacy on cardiac frequency, but no neurological improvement . Another T 3 analogue, triiodothyroacetic acid, is being evaluated in patients with AHDS …”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

Remerand

Boespflug‐Tanguy

Tonduti

et al. 2019

Develop Med Child Neuro

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The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications. What this paper adds Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.

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Section: Discussionmentioning

confidence: 99%

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

Remerand

Boespflug‐Tanguy

Tonduti

et al. 2019

Develop Med Child Neuro

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“…In humans, Triac has a half-life of about 6 hours. Due to its higher affinity for THR and use of different transporters than THs, Triac has been used clinically for patients with RTH syndrome and currently is being tested for patients with MCT8 deficiency (93). When administered to rodents, Triac levels are increased in the liver and induce the expression of T3-regulated target genes (94).…”

Section: Th Metabolites In Lipid Metabolismmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists

Sinha

Bruinstroop

Singh

et al. 2019

Thyroid

175

131

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Background-Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary-THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-L-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions-TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/

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“…with similar potency (Medina-Gómez et al 2004). TRIAC exerts thyromimetic actions on the hypothalamuspituitary-thyroid axis and on peripheral tissues including brain, heart, bone, liver, kidney, adipose tissue and skin, but its exact physiological role is unknown (Groeneweg et al 2017). TRIAC binds efficiently to nuclear TRs (Oppenheimer et al 1973, Smith et al 1980, with a similar affinity as T 3 to TRα1 and a 3-to 6-fold higher affinity than T 3 to TRβ1 and TRβ2 (Schueler et al 1990, Messier & Langlois 2000; and the present data indicate that TRIAC binds to the integrin αvβ3 plasma membrane receptor in endothelial cells, as reported D'Arezzo et al (2004) in L-6 myoblasts.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormones stimulate L-arginine transport in human endothelial cells

Toral¹,

Jiménez

Montoro-Molina

et al. 2018

Journal of Endocrinology

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Thyroid hormone activity is associated with L-arginine metabolism and nitric oxide (NO) production, which participate in the cardiovascular manifestations of thyroid disorders. L-arginine transporters play an important role in activating L-arginine uptake and NO production. However, the effects of thyroid hormones on L-arginine transporters in endothelial cells have not yet been evaluated. We measured L-arginine uptake, mRNA expression of L-arginine transporters, endothelial nitric oxide synthase (eNOS) mRNA and NO generation after the administration of T3, T4, and the T3 analog, 3,3',5-triiodothyroacetic acid TRIAC in human umbilical vein endothelial cells (HUVECs). We also analyzed the role of αvβ3 integrin and of phosphatidyl-inositol-3 kinase (PI3K), mitogen-activated protein kinases (MAPKs: ERK1/2, p38 and SAPK-JNK) and intracellular calcium signaling pathways as underlying mechanisms. To this end, αvβ3 integrin was pharmacologically inhibited by tetraiodothyroacetic acid (TETRAC) or genetically blocked by silencing αv mRNA, and PI3K, MAPKs and intracellular calcium by selective inhibitors. We found that thyroid hormones and the T3 analog TRIAC increased L-arginine uptake in HUVECs, the sodium-independent y+/CAT isoforms, except CAT2b, sodium-dependent y+L system and sodium-independent system b0,+L-arginine transporters, eNOS mRNA; and NO production. These effects were suppressed by αvβ3 integrin inhibition with TETRAC or αv integrin downregulation or by PI3K, MAPK or intracellular Ca2+ signaling inhibitors. We report for the first time that activation of L-arginine uptake by thyroid hormones is related to an up-regulation of L-arginine transporters. This effect seems to be mediated by activation of αvβ3 integrin receptor and subsequent PI3K, MAPK and intracellular Ca2+ signaling pathways.

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Triiodothyroacetic acid in health and disease

Cited by 64 publications

References 189 publications

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations

Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists

Thyroid hormones stimulate L-arginine transport in human endothelial cells

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