The type 3 iodothyronine selenodeiodinase (D3) is an integral membrane protein that inactivates thyroid hormones. By using immunofluorescence cytochemistry confocal microscopy of live or fixed cells transiently expressing FLAG-tagged human D3 or monkey hepatocarcinoma cells expressing endogenous D3, we identified D3 in the plasma membrane. It co-localizes with Na,K-ATPase ␣, with the early endosomal marker EEA-1 and clathrin, but not with two endoplasmic reticulum resident proteins. Most of the D3 molecule is extracellular and can be biotinylated with a cell-impermeant probe. There is constant internalization of D3 that is blocked by sucrose or methyl-␤-cyclodextrin-containing medium. Exposing cells to a weak base such as primaquine increases the pool of internalized D3, suggesting that D3 is recycled between plasma membrane and early endosomes. Such recycling could account for the much longer half-life of D3 (12 h) than the thyroxine activating members of the selenodeiodinase family, type 1 (D1; 8 h) or type 2 (D2; 2 h) deiodinase. The extracellular location of D3 gives ready access to circulating thyroid hormones, explaining its capacity for rapid inactivation of circulating thyroxine and triiodothyronine in patients with hemangiomas and its blockade of the access of maternal thyroid hormones to the human fetus.Thyroid tissue is confined to and is present in all vertebrates. Its role is to synthesize and secrete polyiodinated thyronine molecules that modulate gene expression in virtually every vertebrate tissue through ligand-dependent transcription factors. Thyroxine (T 4 ) 1 is the primary product of thyroid secretion, a pro-hormone that must be activated by deiodination to 3,5,3Ј-triiodothyronine (T 3 ) by either type 1 or 2 iodothyronine deiodinases (D1 or D2) in order to initiate thyroid action. To balance the activation pathway, both T 4 and T 3 are irreversibly inactivated by monodeiodination of the tyrosyl ring of the iodothyronines, a reaction catalyzed by the type 3 iodothyronine deiodinase (D3). These three enzymes constitute a family of selenocysteine (Sec)-containing integral membrane oxidoreductases (1).Changes in the activity of D3 modulate both global and local tissue thyroid status. In the global sense, D3 expression is increased by T 3 and reduced in hypothyroidism or iodine deficiency, thus accelerating or retarding T 3 inactivation to maintain homeostasis (2-4) or to alter plasma T 3 concentrations such as occurs during tadpole metamorphosis or during fetal life (5-7). More complex are the alterations in D3 activity in specific tissues dictated by developmental programs that permit precisely timed changes in their differentiation. For example, during metamorphosis in Xenopus laevis tadpoles, the eyes must shift from a lateral to a more rostral and dorsal location to permit overlapping visual fields. Retinal cells follow this shift with an asymmetrical growth, a process that is thyroid hormone-dependent. To develop asymmetrically, however, a subset of dorsal cells must grow at a slower rate....

HESX1 is a paired-like homeodomain transcription factor that functions as a repressor of PROP1-mediated gene stimulation. Mutations in HESX1 have been implicated in cases of septooptic dysplasia and congenital hypopituitarism. All mutations in HESX1 identified to date have resulted in impaired DNA binding and defective HESX1 action. We have identified a novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding. In turn, this mutation causes increased repression of PROP1-dependent gene activity. These data suggest that enhancement of transcriptional repression during pituitary organogenesis is a novel mechanism for the development of congenital pituitary disorders.

Oxidative stress, caused by an imbalance between antioxidant capacity and reactive oxygen species, may be an early event in a metabolic cascade elicited by a high glycemic index (GI) diet, ultimately increasing the risk for cardiovascular disease and diabetes. We conducted a feeding study to evaluate the acute effects of low-GI compared with high-GI diets on oxidative stress and cardiovascular disease risk factors. The crossover study comprised two 10-day in-patient admissions to a clinical research center. For the admissions, 12 overweight or obese (BMI: 27-45 kg/m 2 ) male subjects aged 18-35 years consumed low-GI or high-GI diets controlled for potentially confounding nutrients. On day 7, after an overnight fast and then during a 5-h postprandial period, we assessed total antioxidant capacity (total and perchloric acid (PCA) protein-precipitated plasma oxygen radical absorbance capacity (ORAC) assay) and oxidative stress status (urinary F 2α -isoprostanes (F 2 IP)). On day 10, we measured cardiovascular disease risk factors. Under fasting conditions, total antioxidant capacity was significantly higher during the low-GI vs. high-GI diet based on total ORAC (11,736 ± 668 vs. 10,381 ± 612 μmol Trolox equivalents/l, P = 0.002) and PCA-ORAC (1,276 ± 96 vs. 1,210 ± 96 μmol Trolox equivalents/l, P = 0.02). Area under the postprandial response curve also differed significantly between the two diets for total ORAC and PCA-ORAC. No diet effects were observed for the other variables. Enhancement in plasma total antioxidant capacity occurs within 1 week on a low-GI diet, before changes in other risk factors, raising the possibility that this phenomenon may mediate, at least in part, the previously reported effects of GI on health.

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