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Thyroid hormone (TH) is crucial for development and metabolism of many tissues. The physiological relevance and therapeutic potential of TH analogs have gained attention in the field for many years. In particular, the relevance and use of 3,3′,5-triiodothyroacetic acid (Triac, TA3) has been explored over the last decades. Although TA3 closely resembles the bioactive hormone T3, differences in transmembrane transport and receptor isoform-specific transcriptional activation potency exist. For these reasons, the application of TA3 as a treatment for resistance to TH (RTH) syndromes, especially MCT8 deficiency, is topic of ongoing research. This review is a summary of all currently available literature about the formation, metabolism, action and therapeutic applications of TA3.
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Cold exposure of mice is a common method to stimulate brown adipose tissue (BAT) activity and induce browning of white adipose tissue (WAT) that has beneficial effects on whole-body lipid metabolism, including reduced plasma triglyceride (TG) concentrations. The liver is a key regulatory organ in lipid metabolism as it can take up as well as oxidize fatty acids. The liver can also synthesize, store and secrete TGs in VLDL particles. The effects of cold exposure on murine hepatic lipid metabolism have not been addressed. Here, we report the effects of 24-h exposure to 4°C on parameters of hepatic lipid metabolism of male C57BL/6J mice. Cold exposure increased hepatic TG concentrations by 2-fold (P < 0.05) but reduced hepatic lipogenic gene expression. Hepatic expression of genes encoding proteins involved in cholesterol synthesis and uptake such as the LDL receptor (LDLR) was significantly increased upon cold exposure. Hepatic expression of Cyp7a1 encoding the rate-limiting enzyme in the classical bile acid (BA) synthesis pathway was increased by 4.3-fold (P < 0.05). Hepatic BA concentrations and fecal BA excretion were increased by 2.8- and 1.3-fold, respectively (P < 0.05 for both). VLDL-TG secretion was reduced by approximately 50% after 24 h of cold exposure (P < 0.05). In conclusion, cold exposure has various, likely intertwined effects on the liver that should be taken into account when studying the effects of cold exposure on whole-body metabolism.
Departments of, Epidemiology and Biostatistics, Internal Medicine, Medical Informatics, The Inspectorate for Health Care, The Dutch Medicines Evaluation Board, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Departments of, Epidemiology and Biostatistics, Internal Medicine, Medical Informatics, The Inspectorate for Health Care, The Dutch Medicines Evaluation Board, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Departments of, Epidemiology and Biostatistics, Internal Medicine, Medical Informatics, The Inspectorate for Health Care, The Dutch Medicines Evaluation Board, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Departments of, Epidemiology and Biostatistics, Internal Medicine, Medical Informatics, The Inspectorate for Health Care, The Dutch Medicines Evaluation Board, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
Departments of, Epidemiology and Biostatistics, Internal Medicine, Medical Informatics, The Inspectorate for Health Care, The Dutch Medicines Evaluation Board, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T4) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T4/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0.8 ms (95% confidence interval (CI) −3.5, 5.2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T4 did not have an increased QTc interval (3.2 ms (95% CI −1.1, 7.6)); stratification on gender showed an increment of 10.9 ms (95% CI 3.4, 18.3) in the fifth quintile in men and 1.1 ms (95% CI −4.2, 6.3) in the fifth quintile of free T4 in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T4 had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2.40 (95% CI 1.20, 4.80)). High levels of free T4 are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T4 is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.
