Abstract
Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug.
Highlights
Thyroid produces two main hormones: L-thyroxine (T4), and L-triiodothyronine (T3)
An antibody-based competitive chemiluminescence immunoassay (CLIA) [202] was used to investigate serum concentration of 3,5-T2 in humans under both physiological and pathophysiological conditions; the results suggested that 3,5-T2 concentrations do not differ in hyperthyroid (0.31 ± 0.02 nm) compared to hypothyroid (0.43 ± 0.04 nm) individuals [202]
Further studies are necessary to better understand the mechanisms underlying these effects, it may be hypothesized that the 3,5-T2 nuclear effects observed in hypothyroid rats are due to SREBP and carbohydrate response element-binding protein (ChREBP), while 3,5-T2 should have an indirect effect, due to its ability to activate a still-unknown pathway leading to SREBP/ChREBP activation
Summary
Thyroid produces two main hormones: L-thyroxine (T4), and L-triiodothyronine (T3). The first one is the predominant form (more than 80%) secreted by the gland and circulating, while T3 is considered the most active form, since it binds with much higher affinity to the nuclear receptors [1,2,3,4,5,6]. As a response to the thyroid-stimulating hormone (TSH), endocytosis (both macro- and micropinocytosis) of thyroglobulin from the apical surface of thyrocytes that line the follicle and fusion of endosomes with lysosomes allow digestion of thyroglobulin by proteases and release of the hormones, as well as of other amino acids, including MIT and DIT (Figure 1) Thyroglobulin functions both as a precursor for TH synthesis and as a storage of inactive hormones in the lumen of follicles. Mutations of MCT8 were already reported to be associated with severe intellectual disability many years ago [50] and, more recently, it was found that mutations in the OATP1C1 transporter associate with severe brain hypometabolism and juvenile neurodegeneration [49,51] These observations demonstrated that serious symptoms of hypothyroidism can be caused by deficits of TH membrane transporters, and the resulting inability of the hormones to enter the cells in sufficient amount
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