Type 1 Iodothyronine Deiodinase Is a Sensitive Marker of Peripheral Thyroid Status in the Mouse

Abstract

Mice with one thyroid hormone receptor (TR) alpha-1 allele encoding a dominant negative mutant receptor (TR alpha1(PV/+)) have persistently elevated serum T3 levels (1.9-fold above normal). They also have markedly increased hepatic type 1 iodothyronine deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T3-responsive genes, such as Spot14 and mitochondrial alpha-glycerol phosphate dehydrogenase (alpha-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TR alpha1+/+). To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3. Hypothyroidism decreased hepatic D1, Spot14, and alpha-GPD mRNA to similar levels in TR alpha1+/+ and TR alpha1(PV/+) mice, whereas T3 administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and alpha-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 iodothyronine deiodinase activity was 3 times greater in the TR alpha1(PV/+) mice, and these mice had no T3-dependent induction of type 3 iodothyronine deiodinase. Thus, the marked responsiveness of hepatic D1 to T3 relative to other genes, such as Spot14 and alpha-GPD, explains the relatively large effect of the modest increase in serum T3 in the TR alpha1(PV/+) mice, and TR alpha plays a key role in T3-dependent positive and negative regulation of the deiodinases in the cerebral cortex.

The effect of low dose lipopolysaccharide on thyroid hormone-regulated actin cytoskeleton modulation and type 2 iodothyronine deiodinase activity in astrocytes

“…The half life of D2 activity is only ~40 min and T4 rapidly decreases the activity without affecting its mRNA level [24,26,35]. In the present study, 10 nM T4 significantly suppressed D2 activity in C6 cells (Fig.…”

“…On the assay day, samples were collected in lysis buffer (0.1 M phosphate and 1 mM EDTA at pH 6.9 with 10 mM dithiothreitol and 0.25 M sucrose). After sonication, 75 μg protein of each sample was used for D2 assay as previously described [35,36]. Samples were incubated in 75 µL of reaction buf-no significant difference between T4 (+) and LPS (+) T4 (+) p38 inhibitor (+).…”

Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior

“…Thyroidectomized rats, both untreated and treated, were fed a low iodine diet starting the day of surgery. 21 At the time of killing, both P95 and P120 thyroidectomized rats had greatly decreased T4 and T3 in serum and liver (serum T4 < 1.1 ng/ml and T3 < 0.08 ng/ml; liver T4 < 2.1 ng/g and T3 < 0.70 ng/g), a significant reduction in body weight (BW; P < 0.001), and a 66% reduction of liver type 1 deiodinase (D1) mRNA expression 32 with respect to sham-operated controls. TH treatment consisted in the administration of a physiological combination of T4 and T3 in the drinking water (0.18 mg T4/ml and 0.03 mg T3/ml).…”

Coupling between Nutrient Availability and Thyroid Hormone Activation

“…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 .…”