The Influence of Fasting, Diabetes, and Several Pharmacological Agents on the Pathways of Thyroxine Metabolism in Rat Liver

Balsam, Alan; Ingbar, Sidney H.; Sexton, Franklin

doi:10.1172/jci109143

Cited by 173 publications

(63 citation statements)

References 34 publications

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“…However, it is less clear whether the extrathyroidal T 3 production is reduced as well. Whereas hepatic D1 activity is reduced during caloric restriction in rodents (11), this seems to be a consequence rather than a cause of the low serum T 3 , given that Dio1 is highly responsive to T 3 (8,12). On the other hand, D2 is normally stimulated during hypothyroidism (7), and the fact that it is reduced by fasting in the pituitary gland and brown * This work was supported in part by National Institutes of Health, NIDDK, adipose tissue (BAT) (10) indicates a role in the fall of serum T 3 .…”

mentioning

confidence: 97%

Coupling between Nutrient Availability and Thyroid Hormone Activation

Lartey

Werneck-de-Castro

O-Sullivan

et al. 2015

Journal of Biological Chemistry

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Background: Insulin/IGF-1 stimulates thyroid hormone action via type 2 deiodinase (D2). Results: Insulin/IGF-1-induced activation of the PI3K-mTORC2-Akt pathway transcriptionally up-regulates D2. Conclusion: FOXO1 represses DIO2 during fasting, and derepression occurs via nutritional activation of the PI3K-mTORC2-Akt pathway. Significance: This mechanism explains how T 3 production, serum T 3 levels, and T 3 -dependent cellular metabolic rate are kept at a level proportionate to the availability of energy substrates.

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mentioning

confidence: 97%

Coupling between Nutrient Availability and Thyroid Hormone Activation

Lartey

Werneck-de-Castro

O-Sullivan

et al. 2015

Journal of Biological Chemistry

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“…HTA was most commonly used for studies of '251-fl-T4 or '25I-#-T3 metabolism, and BAW for studies of '25I-U-T4, 125I-U-T3, and labeled DIT metabolism. Radioiodine-labeled compounds were identified by staining of marker compounds and were quantitated by methods previously described (11).…”

mentioning

confidence: 99%

Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism.

Balsam¹,

Sexton²,

Borges³

et al. 1983

J. Clin. Invest.

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A B S T R A C T Studies were performed to elucidate the nature of the pathway of hepatic thyroxine (T4) metabolism that is activated by inhibitors of liver catalase. For this purpose, the metabolism of T4 in homogenates of rat liver was monitored with T4 labeled with '25I either at the 5'-position of the outer-ring ('251-#-T4) or uniformly in both the outer and inner rings (125I-U-T4). In homogenates incubated with 125I-0-T4 in an atmosphere of 02, the catalase inhibitor aminotriazole greatly enhanced T4 degradation, promoting the formation of large proportions of '25I-labeled iodide (125I1 I-) and chromatographically immobile origin material (1251-OM), but only a minute proportion of '25I-labeled 3,5,3'-triiodothyronine ('25I-T3) (T3 neogenesis). In an atmosphere of N2, in contrast, homogenates produced much larger proportions of 1251-T3, and aminotriazole had no effect. In incubations with 125I-U-T4, under aerobic conditions, control homogenates degraded T4 slowly; formation of 1251-labeled 3,5-diiodotyrosine ('25I-DIT) was seen only occasionally and in minute proportions. However, in homogenates incubated under 02, but not N2, aminotriazole consistently elicited the formation of large proportions of 1251-DIT, indicating that the ether link of T4 was being cleaved by an 02-dependent process.Formation of 125j-DIT in the presence of aminotriazole and 02 was markedly inhibited by the substrates of peroxidase, aminoantipyrine, and guaiacol. GSH greatly attenuated the increase in DIT formation induced by aminotriazole, whereas the sulfhydryl inhibitor N-ethylmaleimide (NEM) activated the DIT-generating pathway, even in the absence of aminotriazole.This work has been published in abstract form in 1979, Clin. Res., 27:247A.Received for publication 18 May 1982 and in revised form 3 May 1983. Activation of the in vitro formation of 125I-DIT from 125I-U-T4was also produced by the in vivo administration of aminotriazole or bacterial endotoxin, an agent that reduces hepatic catalase activity. Studies with 125I-DIT as substrate revealed it to be rapidly deiodinated by liver homogenates under aerobic conditions. Recovery of 125I-DIT from 125I-U-T4 was increased by the addition of the inhibitor of iodotyrosine dehalogenase, 3,5-dinitrotyrosine. However, as judged from studies conducted in parallel with radioiodinelabeled DIT and 1251-U-T4 as substrates, none of the factors that altered the proportion of 1251-DIT found after incubations with 125I-U-T4 did so by altering the degradation of the 125I-DIT formed.The factors that influenced DIT formation from T4 in rat liver had opposite effects on T3 neogenesis. Thus, aminotriazole, endotoxin, NEM, and an aerobic atmosphere, all of which enhanced DIT formation, were inhibitory to T3 neogenesis. In contrast, anaerobiosis and GSH inhibited ether-link cleavage of T4, but facilitated T3 neogenesis.The foregoing results suggest that a pathway for the ether-link cleavage of T4 to yield DIT is present in rat liver. Activity of this pathway, which appears to be peroxidase mediated, i...

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“…Most of these studies, however, were performed using crude liver homogenate under quite unphysiological conditions. Although a few studies used liver slices (15) and perfused liver (14), their limited viability, several hours at most, make them unsuitable in an investigation of the regulatory mechanism of the starvation effect, which takes place in days rather than hours (1)(2)(3)(4)(5). This disadvantage can be resolved by using primary cultured adult rat hepatocytes (16), which also offer the advantage of cellular homogeneity, the opportunity to conduct experiments with homologous cells from a single rat, and especially the ability to study the effect of various nutrients or hormones without the secondary hormonal responses from other organs, as can occur in whole animial studies.…”

mentioning

confidence: 99%

Thyroid hormone metabolism in primary cultured rat hepatocytes. Effects of glucose, glucagon, and insulin.

Sato¹,

Robbins²

1981

J. Clin. Invest.

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A B S T R A C T Primary cultured adult rat hepatocytes were used to study the regulation of thyroid hormone deiodination. Control studies showed that these cells survived for at least 4 d, during which time they actively deiodinated both the phenolic (5'-) and nonphenolic (5-) rings of L-thyroxine (T4),3,5,3'-triiodo-L-thyronine, and 3,3',5'-triiodothyronine. Increasing the substrate concentration caused a decrease in fractional iodide release and a corresponding increase in conjugation with sulfate and glucuronide. Propylthiouracil strongly inhibited the 5'-deiodinase activity and caused only a slight decrease in 5-deiodinase activity. Thus, these monolayer-cultured cells preserved many of the properties of normal hepatocytes. Incubation with combinations of insulin, glucagon, and/or glucose for 5 h showed that insulin stimulated T4 5'-deiodination, whereas glucagon inhibited the insulin stimulation but had no effect in the absence of insulin. Glucose had no effect and did not alter the effect of the hormones. The insulin-enhanced deiodination increased between 1 and 5 h, which suggests that the previous inability to demonstrate an insulin effect was due to the short survival of the in vitro liver systems used in those studies. The present data suggest that the inhibition of T4 5'-deiodination observed during fasting, and its restoration by refeeding, mnay be related to the effects offeeding on insulin and glucagon release rather than on glucose per se.

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The Influence of Fasting, Diabetes, and Several Pharmacological Agents on the Pathways of Thyroxine Metabolism in Rat Liver

Cited by 173 publications

References 34 publications

Coupling between Nutrient Availability and Thyroid Hormone Activation

Coupling between Nutrient Availability and Thyroid Hormone Activation

Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism.

Thyroid hormone metabolism in primary cultured rat hepatocytes. Effects of glucose, glucagon, and insulin.

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