Excess Iodine and High-Fat Diet Combination Modulates Lipid Profile, Thyroid Hormone, and Hepatic LDLr Expression Values in Mice

The aim of this study was to illustrate the combined effect of excess iodine and high-fat diet on lipid metabolism and its potential molecular mechanism. Sixty Balb/c mice were randomly allocated to three control groups or three excess iodine groups and fed with a high-fat diet in the absence or presence of 1,200 μg/L iodine for 1, 3, or 6 months, respectively. Serum lipid parameters and serum thyroid hormones were measured. Expressions of scavenger receptor class B type-I (SR-BI) and low density lipoproteins receptor (LDLr) mRNA and protein in liver were detected. Thyroid histology and liver type 1 iodothyronine deiodinase activity were analyzed. At the end of 3 and 6 months, compared with control, serum TC, TG, and LDL-C in excess iodine group were significantly lower (p < 0.05). LDLr expression in liver was increased significantly (p < 0.05) and parallel to the change of serum TC and TG. TT3 and TT4 levels in serum were elevated and TSH decreased significantly (p < 0.05). Liver type I iodothyronine deiodinase activity was significantly higher (p < 0.05) than control at the end of 6 months. Moreover, a time course damage effect of excess iodine combined with high-fat diet on thyroid glands was observed. The present findings demonstrated that excess iodine combined with high-fat diet could cause damage to thyroid glands and lead to thyroid hormone disorder. Those in turn caused the upregulation of hepatic LDLr gene, which resulted in the disorder in serum lipids.     

Thyroid function and deiodinase activities in rats with marginal iodine deficiency

The hypothesis tested was whether marginal iodine deficiency for a period of 6 wk affects iodothyronine deiodinase activities in liver and brain of rats. Male rats were fed purified diets either deficient or sufficient in iodine; the diets were fed on a restricted basis (60% ofad libitum intake). Body weight gain of the two groups was comparable. Iodine deficiency was evidenced by increased thyroid weight (26%), reduced urinary iodine excretion (80%), and reduced plasma T₄ concentrations (22%). Activities of liver type I and brain type III deiodinase were unchanged, but the activity of type II deiodinase in brain was increased (28%) in the iodine-deficient rats. Food restrictionper se significantly lowered T₃ (30%) and T₄ (22%) concentrations in plasma and decreased type III deiodinase activity in brain (30%). These results indicate that in marginal iodine deficiency the activities of hepatic type I deiodinase and brain type III deiodinase are unchanged, whereas that of brain type II deiodinase is increased.     

Effect of age on sexually dimorphic selenoprotein expression in mice

Clinical data suggest that selenium (Se) supplementation decreases disease predisposition and severity and accelerates recovery in a variety of pathologies. Pre-supplementation Se levels and sex represent important determinants of these Se-dependent health effects. Accordingly, we previously reported on sexually dimorphic expression patterns of Se-dependent glutathione peroxidase 1, type I deiodinase, and selenoprotein P in young mice. In the present study we investigated whether these differences vary with age. The strong sexual dimorphic expression of hepatic type I deiodinase that was observed in young mice vanished both at the mRNA and enzyme activity level by 1 year of age. In contrast, the strong sex-specific differences in renal type I deiodinase mRNA expression were sustained with age. Accordingly, deiodinase enzymatic activities differed in male and female kidneys, largely independent of age [average of 6.8 vs. 15.7 pmol/(min mg) in males vs. females]. In parallel, hepatic Se concentrations and glutathione peroxidase activities increased in female mice compared to male littermates, establishing a new sexual dimorphism in liver. Thus, age represents another important modifier of the dynamic sex- and tissue-specific selenoprotein expression patterns. These data highlight again the unique physiological regulatory mechanisms that have evolved to control Se metabolism according to the actual needs of the organism.     

Iodothyronine 5'-deiodinase activity in rat brown adipose tissue during development

Iodothyronine 5'-deiodinase activity in rat brown adipose tissue has a characteristic pattern of developmental changes that is completely different from that of the liver. Fetal brown fat exhibits an extremely high iodothyronine 5'-deiodinase activity that is approx. 10-fold that in adult rats. Even though brown fat iodothyronine 5'-deiodinase activity falls suddenly at birth, there is a new peak in the activity around days 5-7 of life, whereas it remains very low afterwards. Just after birth, brown adipose tissue iodothyronine 5'-deiodinase activity is already capable of stimulation by noradrenaline. The postnatal peak in brown fat iodothyronine 5'-deiodinase correlates with the known increase in the thermogenic activity of the tissue in the neonatal rat, thus reinforcing the suggestion that local 3',3,5-triiodothyronine generation could be an important event related to thermogenesis in brown adipose tissue. However, the high fetal activity was only slightly related to the thermogenic activity of brown fat. Moreover, the increased iodothyronine 5'-deiodinase activity of brown adipose tissue during fetal and neonatal life suggests a substantial contribution by brown fat in the overall extrathyroidal 3',3,5-triiodothyronine production in these physiological periods.     

Sex steroids modulate rat anterior pituitary and liver iodothyronine deiodinase activities.

In this study, we investigated the sex hormone regulation of 5'-iodothyronine deiodinase activity, which is responsible for enzymatic conversion of thyroxine into the bioactive form, triiodothyronine. Pituitary homogenates and liver microsomes from: 1) ovariectomized rats injected with 17-beta-estradiol benzoate and/or progesterone (0.7 and 250 microg/100 g body weight, respectively, subcutaneously, over 10 days); 2) male castrated rats treated or not with 0.4 mg/100 g body weight testosterone propionate, intramuscular, over 7 days, were assayed for type 1 and type 2 deiodinase activity in the pituitary. Enzyme activities were measured by release of (125)I from deiodination of (125)I reverse triiodothyronine under varying assay conditions. Estrogen stimulated anterior pituitary and liver type 1 deiodinase activity in ovariectomized rats (45 and 30 %, p < 0.05). Progesterone inhibited the liver enzyme (40 %, p < 0.05), and had no effect on the pituitary, but in both tissues, blocked estrogen stimulatory effect on type 1 deiodinase. In males, testosterone normalized the reduced liver type 1 deiodinase of castrated rats. However, in the pituitary, castration increased (50 %) type 1 deiodinase independent of testosterone treatment, suggesting the existence of a inhibitory testicular regulator of pituitary type 1 enzyme. Treatments did not alter pituitary type 2 deiodinase activity. In conclusion, gonads and sex steroids differentially modulate type 1 deiodinase activity in rat pituitary and liver.     

Iodothyronine 5′-deiodinase activity in rat brown adipose tissue during development

Iosothyronine 5′-deiodinase activity in rat brown adipose tissue has a characteristic pattern of developmental changes that is completely different from that of the liver. Fetal brown fat exhibits an extremely high iodothyronine 5′-deiodinase activity that is approx. 10-fold that in adult rats. Even though brown fat iodothyronine 5′-deiodinase activity falls suddenly at birth, there is a new peak in the activity around days 5–7 of life, whereas it remaines very low afterwards. Just after birth, brown adipose tissue iodothyronine 5′-deiodinase activity is already capable of stimulation by noradrenaline. The postnatal peak in brown fat iodothyronine 5′-deiodinase correlates with the known increase in the thermogenic activity of the tissue in the neonatal rat, thus reinforcing the suggestion that local 3′,3,5-triiodothyronine generation could be an important event related to thermogeneis in brown adispose tissue. However, the high fetal activity was only slightly related to the thermogenic activity of brown fat. Moreover, the increased iodothyronine 5′-deiodinase activity of brown adipose tissue during fetal and neonatal life suggests a substantial contribution by brown fat in the overall extrahydroidal 3′,3,5-triiodothyronine production in these physiological periods.     

Comparing functional metabolic effects of marginal and sufficient selenium supply in sheep

This study was performed to characterise key data of long-term ovine Se metabolism and to work out the best biomarker of Se status. An upgrade from marginal (<0.05 mg Se/kg diet, ‘Se?’) to sufficient (0.2 mg Se/kg diet, ‘Se+’) nutritional Se supply using sodium selenite was monitered biweekly by analysing Se concentration, glutathione peroxidase (Gpx) activity and routine biochemistry in blood/serum over 2 years. Se, Cu, Zn, cytosolic Gpx and thioredoxin reductase (TrxR) activity were measured in the liver (biopsies/post-mortem). Se, Gpx, TrxR, glutathione-S-transferase-alpha (aGST) and iodothyronine deiodinase (Dio1) were analysed in the kidney, heart muscle and thyroid. Relative mRNA expression of hepatic aGST1 and Gpx1 was determined.Improvement of Se supply strongly increased serum and liver Se concentration within 10 and 20 days, respectively followed by a plateau. Whereas the achievement of a maximum whole blood Gpx activity was reached after 3 months, serum Gpx3 activity increased with high variations. Hepatic Gpx activity reached a maximum during days 100–200, decreasing thereafter. Distinct group differences in Se and cytosolic Gpx activity were evident in all organs (except Se in kidney). TrxR and Dio1 activity was affected only in the liver. The Se? sheep showed an ongoing decrease in serum Se concentration within 2 years, whereas liver Se remained almost unaffected. High relative Gpx1 mRNA expression in the Se+ group was consensual to high hepatic Gpx activity. Relative mRNA expression of hepatic aGST1 was higher in the Se? sheep. Clinical signs and abnormalities in routine biochemistry were absent.In summary, the best biomarker of Se deprivation and nutritional Se upgrade, respectively was Se in serum. Moreover, hepatic Se concentrations reliably reflected the upgrade of Se supply within days. Whole blood Gpx reacts slowly depending on newly formed erythrocytes restricting its diagnostic use. Vital organs are affected by Se deficiency due to a decrease of cytosolic Gpx activity attenuating the antioxidative system. Cellular up-regulation of aGST1 mRNA expression in the Se? group is assumed to partially compensate for the decreased antioxidant defence due to a loss in Gpx activity. This sheep model appears advantageous for long-term studies on sub-clinical metabolic effects in experimental modifiable nutritional Se supply.     

Apolipoprotein-E-gene expression in rat liver during development in relation to insulin and glucagon

An apolipoprotein-E (apo-E) cDNA probe, cloned by immunoscreening of a lambda GT11 rat liver cDNA library, was used to further characterize the expression of the apo-E gene in rat liver during development, in relation to plasma insulin and glucagon levels. The apo-E mRNA level was low in fetus liver, then abruptly increased at birth and rose further during the suckling period. It returned to the level at birth in 10-week-old adults. These variations were paralleled with dramatic changes in plasma glucagon, which rose at birth and remained high during suckling. At the same time, the insulin/glucagon molar ratio fell. Administration of N6,O2-dibutyryl cAMP to 5-day-old rats resulted in a significant induction of liver apo-E mRNA. Moreover, liver apo-E mRNA rose in 10-h-fasted suckling rats as compared to controls, while plasma glucagon increased and the insulin/glucagon ratio decreased. Conversely, glucose feeding of suckling rats did not induce any increase in liver apo-E mRNA, the insulin/glucagon ratio was 10-fold higher than in fasted animals. Our results are consistent with liver apo-E gene expression being under the control of plasma glucagon and of the glucagon/insulin balance.     

Differential gene expression of organic anion transporters in male and female rats.

Sex-related differential gene expression of organic anion transporters (rOAT1, rOAT2, and rOAT3) in rat brain, liver, and kidney was investigated. There were no sex differences in the expression of rOAT1 mRNA. rOAT2 mRNA was abundant in the liver and weakly expressed in the kidney of male rats; however, the OAT2 gene was strongly expressed in both organs of females. The abundance of rOAT2 mRNA markedly increased in castrated male rat kidney; however, treatment of castrated male rats with testosterone led to a decrease of rOAT2 mRNA. Expression of rOAT3 mRNA in intact female rats was found in the kidney and brain, whereas in males rOAT3 mRNA was also found in the liver. rOAT3 mRNA markedly decreased in the liver of castrated male rats but increased in testosterone-treated castrated male rats. Moreover, rOAT3 mRNA increased in the hypophysectomized female rat liver, indicating that rOAT3 is an inducible isoform. The present findings suggest that sex steroids play an important role in the expression and maintenance of OAT2/3 isoforms in the rat liver and kidney. Our results provide information on the differential gene expression of OAT isoforms with sex hormone dependency.     

Kinetics and thiol requirements of iodothyronine 5'-deiodination are tissue-specific in common carp (Cyprinus carpio L.)

Iodothyronine deiodinases determine the biological activity of thyroid hormones. Despite the homology of the catalytic sites of mammalian and teleostean deiodinases, in-vitro requirements for the putative thiol co-substrate dithiothreitol (DTT) vary considerably between vertebrate species. To further our insights in the interactions between the deiodinase protein and its substrates: thyroid hormone and DTT, we measured enzymatic iodothyronine 5′-deiodination, Dio1 and Dio2 mRNA expression, and Dio1 affinity probe binding in liver and kidney preparations from a freshwater teleost, the common carp (Cyprinus carpio L.). Deiodination rates, using reverse T3 (rT3, 3,3′,5′-triiodothyronine) as the substrate, were analysed as a function of the iodothyronine and DTT concentrations. In kidney rT3 5′-deiodinase activity measured at rT3 concentrations up to 10 μM and in the absence of DTT does not saturate appreciably. In the presence of 1 mM DTT, renal rT3 deiodination rates are 20-fold lower. In contrast, rT3 5′-deiodination in liver is potently stimulated by 1 mM DTT. The marked biochemical differences between 5′-deiodination in liver and kidney are not associated with the expression of either Dio1 or Dio2 mRNA since both organs express both deiodinase types. In liver and kidney, DTT stimulates the incorporation of N-bromoacetylated affinity labels in proteins with estimated molecular masses of 57 and 55, and 31 and 28 kDa, respectively. Although primary structures are highly homologous, the biochemistry of carp deiodinases differs markedly from their mammalian counterparts.     

Levels of metallothionein messenger RNA in foetal, neonatal and maternal rat liver

We have used translation in vitro of hepatic polyadenylated RNA to characterize the levels of metallothionein mRNA in foetal, neonatal, pregnant and nulliparous rats. The translation products of foetal hepatic metallothionein mRNA increased relative to other mRNA translation products from day 18 of gestation to birth and attained a maximum, maintained throughout suckling, which is tenfold above 17-day foetal hepatic levels and fourfold above adult levels. Maternal liver metallothionein mRNA decreased fivefold between 17 days and 20 days of gestation, rose sharply immediately before birth, and was low throughout lactation.     

Pulsatile growth hormone secretion decreases S-adenosylmethionine synthetase in rat liver

S-adenosylmethionine synthetase (AdoMet synthetase) is responsible for the synthesis of the major methyl donor S-adenosylmethionine. The AdoMet synthetase gene was identified by subtractive suppressive hybridization as being expressed at higher levels in the liver of rats continuously exposed to growth hormone (GH) than in rats intermittently exposed to the hormone. Further studies on the regulation of AdoMet synthetase showed that the activity and mRNA levels were higher in female than in male rats. Hypophysectomy increased AdoMet synthetase mRNA in both male and female rats. Combined thyroxine and cortisol treatment of hypophysectomized rats had no effect on AdoMet synthetase mRNA levels. Two daily injections of GH for 7 days, mimicking the male secretory pattern of GH, decreased AdoMet synthetase activity and mRNA levels. A continuous infusion of GH, mimicking the female secretory pattern of GH, had small or no effects on AdoMet synthetase activity and decreased the mRNA levels to a lesser degree than two daily injections. It is concluded that the lower AdoMet synthetase activity in male rats is due to an inhibitory effect of the male characteristic pulsatile secretory pattern of GH on AdoMet synthetase mRNA expression.