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The properties of nuclear receptors belonging to the superfamily of receptors acting as transcription factors are modulated by nutritional and hormonal conditions. We showed recently that retinoic acid (RA) restored to normal the expression of receptors attenuated by hypothyroidism. The present study was designed to find out whether dietary vitamin A (as retinol) had the same effect. Propylthiouracil in drinking water induced both hypothyroidism and a vitamin A-deficient status in rats. The maximum binding capacity (Cmax) of triiodothyronine nuclear receptors (TR) was unchanged, while that of nuclear RA receptors (RAR) and nuclear glucocorticoid hormone receptors (GRn) was reduced in the liver of these hypothyroid rats. The reduced Cmax of RAR stemmed from a lower level of RAR mRNA, while the reduced Cmax of GRn was assumed to be due to reduced translocation of the receptor from the cytosol to the nucleus. Feeding the hypothyroid rats with a vitamin A-rich diet did not restore the Cmax of either RAR or GRn to normal. The lack of effect of dietary retinol on RAR expression may be attributed to either genomic (unoccupied TR block the expression of RAR genes) and/or extragenomic (hypothyroidism decreases the availability of retinol and/or its metabolism to RA) mechanisms. Triiodothyronine is thought to favour the translocation of glucocorticoid hormone receptors from cytosol to nucleus. These findings provide more information on the relationship between vitamin A and hormonal status, showing that a vitamin A-rich diet is without apparent effect on the expression of nuclear receptors in hypothyroid rats. [ABSTRACT FROM PUBLISHER]

Objective: The type of dietary fat as well as the amount of cholesterol occurring in the diet have been associated with several metabolic disorders. Thus, the aim of the present study was to investigate the influence of a hypercholesterolemic diet enriched with coconut oil and cholesterol on carbohydrate and lipid metabolism in a rat model., Methods: Twenty male Wistar rats weighing about 190 g were assigned to two dietary groups. One group received a semipurified control diet and the other was given a diet enriched in coconut oil (25% by weight) and cholesterol (1% by weight) for 26 days., Results: Our results indicated a significant increase in serum total cholesterol (+285%; p<0.001), low-density lipoproteins (+154%; p<0.01), liver cholesterol (+1509%; p<0.001), as well as a significant increase in liver weight (+46%; p<0.001) in those rats fed the hypercholesterolemia-inducing diet as compared to controls. Moreover, a significant decrease in serum high-density lipoproteins (-67%; p<0.001), triacylglycerols levels (-33%; p<0.05), and abdominal fat weight (-39%; p<0.01) were found. The observed alterations in serum lipid and lipoprotein profile resembled a situation of type IIa hyperlipidemia in humans. Measurement of several enzymes concerned with lipid utilization revealed a significant increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity (+68%; p<0.01) in the liver of animals fed the hypercholesterolemic diet, while a significant reduction in plasma lecithin-cholesterol acyltransferase activity (-66%; p<0.001) was found. The situation of hypoglycemia (-18%; p<0.05) was accompanied by lower levels of serum insulin (-45%; p<0.01) and liver glycogen (-30%; p<0.05) in the hypercholesterolemic rats. Furthermore, glucose utilization was altered since lower glucose-6-Pase (-33%; p<0.05) and increased glucokinase (+212%; p<0.001) activities in the liver were found in the rat model of hypercholesterolemia., Conclusion: These results provide new evidence that a diet-induced hypercholesterolemia in rats is associated with several adaptative changes in carbohydrate metabolism. These findings may be of importance not only considering the role of western diets on cholesterogenesis, but also in other metabolic disturbances involving lipid and carbohydrate metabolism.

Several studies have shown that dietary factors modulate cell signaling pathways. The aim of this study was to determine whether a hypercholesterolemia-inducing diet rich in saturated fat and cholesterol modifies rat liver expression of the nuclear receptors of retinoic acid (RAR), triiodothyronine (TR), and glucocorticoid hormone (GR), which are transcriptional factors. The experimental diet contained coconut oil 25 g/100 g as a source of lipids, cholesterol 1 g/100 g, and cholic acid 0.5 g/100 g, and the control diet contained olive oil 5 g/100 g. After 26 days of feeding the hypercholesterolemia-inducing diet, a lower binding capacity of the nuclear receptors and a smaller amount of their mRNA were observed. Moreover, the activities of malic enzyme (ME) and tyrosine aminotransferase (TAT), whose gene promotors contain a response element to TR and GR, respectively, were significantly decreased. These changes occurred in a cellular environment characterized by a high level of cholesterol and free fatty acids (FFAs). Thus, two nonexclusive hypotheses can be proposed to explain this decreased expression of nuclear receptors, one emphasizing the effect of lipidic components on the cellular amount of receptor ligands (retinoic acid [RA] and triiodothyronine [T3]), the other emphasizing a modification of the balance between nuclear receptors that could impede the upregulation of TR and RAR.

In a previous study, we showed that a high-fat diet, rich in saturated fatty acids and cholesterol, induced hypercholesterolemia and, in rat liver, a decreased expression of TR and RAR, nuclear receptors which are transcription factors for genes involved in cell growth, differentiation and cellular homeostasis. The aim of this study was to determine whether hypercholesterolemia plays a role in the onset of this decreased expression. Rats were fed a high-fat diet, rich in saturated fatty acids and cholesterol, for 3 weeks and then received in addition Vicia faba for 2 weeks. The inclusion of the legume induced a decrease in hypercholesterolemia (in agreement with numerous data) but did not affect the underexpression of TR or RAR (expression evaluated as the maximum binding capacity of receptors and as the abundance of mRNA of these receptors). Thus, it is suggested that, at least in this experimental model, hypercholesterolemia plays a minor role in the decreased expression of nuclear receptors in rat liver.

The binding capacity (Cmax) of the glucocorticoid hormone receptor (GR) was affected by vitamin A status in rat liver. In rats fed on a vitamin A-overloaded diet as well as in rats administered with retinoic acid (RA) there was an increased ratio Cmax of nuclear GR (expressed as fmol/mg liver): Cmax of cytosolic GR (expressed as fmol/mg liver) while in rats fed on a vitamin A-deficient diet this ratio was decreased. These results suggested that an increased amount of RA, resulting from either metabolization of an increased amount of dietary retinol or RA administration, enhanced the translocation of GR from the cytosolic compartment to the nuclear compartment. Moreover such an increased amount of RA could also induce the observed decreased Cmax of the total GR that we observed. These observations were similar to the well known effects of dexamethasone administration on the properties of GR. It is probable that RA, similarly to dexamethasone treatment, induces a dissociation of the tetrameric form of the cytosolic GR and thus enhances translocation of the monomeric form from cytosol to nucleus and also resulting in an increased proteolytic degradation of the receptor.

Triiodothyronine (T3) receptors (TRs) and retinoic acid (RA) receptors (RARs) exert their effects on growth, differentiation and cellular homeostasis by acting as transcription factors. The binding characteristics of these receptors have been studied in liver of hypothyroid and hyperthyroid rats, with or without treatment with T3, RA or T3 + RA together. The changes in binding induced by RA treatment depended on the hormonal status of the rat. In hypothyroid rats the T3 binding capacity was unaltered by administration of T3 or RA alone but increased by 48% after treatment with T3 and RA together. In these rats administration of RA, T3 or T3 + RA increased the RAR binding capacity by 45, 79 and 112%, respectively. In hyperthyroid rats the administration of RA reduced the TR and RAR binding capacities by 22 and 37%, respectively. We found also that the affinity constants of TRs and RARs were reduced in hypothyroid rats after treatment with T3 or T3 + RA. It is suggested that this change of the properties of receptors is related to a ligand-dependent conformational change in these receptors.

Properties of retinoic acid receptors and glucocorticoid receptors of rat liver were influenced by retinol status in a nonsimilar manner. The binding of the retinoic acid receptors which was lowered in vitamin A--deficient animals relative to controls was restored by a single dose (100 micrograms) of retinoic acid; in vitamin A--overloaded animals (40-fold the control intake) the binding was greater than in controls. The binding of the glucocorticoid receptor was higher in vitamin A--deficient rats than in controls and restored by retinoic acid supplementation, but did not differ from controls in the vitamin A--overloaded rats. The cellular actions of glucocorticoid hormone and retinoic acid were investigated by assaying the activity of some related enzymes. The activity of tyrosine aminotransferase reflected glucocorticoid receptor binding in vitamin A--deficient and vitamin A--restored rats. The decreased tyrosine amino transferase activity observed in vitamin A--overloaded rats could be related to the inhibition of expression of tyrosine amino transferase gene by retinoic acid. Alcohol dehydrogenase activity was unaffected or only slightly affected by vitamin A status. The known existence of glucocorticoid hormone- and retinoic acid--sensitive elements in the alcohol dehydrogenase gene could explain such observations. Furthermore, the changes in the binding of retinoic acid receptors and glucocorticoid receptors were often in opposite directions. These results provide new evidence for the mechanisms by which the amount of dietary vitamin A modulates hormonal status.

Weaned male rats were fed a 4 ppm selenium diet. Compared after 2 mo with a control group fed a 0.4 ppm diet, the rats' body weights had not significantly decreased and liver function was normal, but portal pressure was 1.8 times higher (p less than 0.05). Liver weight was slightly increased (10.3%; p less than 0.05). All livers had an abnormal appearance. In the less severe cases the surface was only slightly irregular, but in the more severe cases, atrophic micronodular lobes and hypertrophic lobes, with mildly irregular surfaces, were present. On light microscopy, atrophic lobes displayed a peripheral nodular zone with micronodules separated by rows of atrophic hepatocytes without fibrosis, characteristic of nodular regenerative hyperplasia, and a central atrophic zone that was sometimes peliotic. Hypertrophic lobes and livers in the less severe cases had only minor and relatively localized evidence of nodular regenerative hyperplasia; occasional peliosis was seen. In all cases portal veins, hepatic veins and hepatic arteries were normal. By electron microscopy, in nonnodular zones with no obvious evidence of parenchymal atrophy, the endothelial wall showed signs of complete or incomplete capillarization with frequent enlargement of the Disse space. The selenium-enriched diet is a reproducible model of liver nodular regenerative hyperplasia. In this model, damage to the sinusoidal wall could represent the primum movens of microcirculatory disturbances.

The plasmatic rate of Ca, Na and K are nearly constant during the deep lethargy of hedgehogs, common dormice and garden dormice and little differ from those measured in the active animals at 22 degrees C. Only the kaliemies of the hibernating common dormice and garden dormice are very low. The evolution of the three parameters during the alternance lethargy and periodic arousal has been analysed in terms of the metabolic and endocrinian changes which occur at those moments.

Basal serum TSH concentrations and TRH-induced TSH response were studied in control and in vitamin A-deficient rats at different times between the fifth week on diet (when growth of deficient animals was still normal) and the beginning of the weight plateau (as soon as growth of deficient animals had stopped). In deficient rats the TSH values were always lower than in the control rats. TRH injections (50 ng/100 g b.w.) in anaesthetized animals (amobarbital 1 mg/100 g b.w.) resulted in an approximately 12-fold increase in serum TSH levels within 6 minutes. The TSH levels remained elevated for at least 15 minutes and were similar in control and deficient rats. We hypothesize that the lower basal serum TSH concentrations are the result of a feedback mechanism triggered by an increase of serum free thyroxine (FT4) and free triiodothyronine (FT3).

Some aspects of thyroid hormone metabolism were studied in rats on a vitamin A-deficient diet for 7-8 weeks. It was shown that, in deficiency, thyroxinemia, the extrathyroidal thyroxine (T4) pool and the T4 biological half-life were increased, and the T4 distribution space and the T4 disposal rate were similar to those in control rats. The in vitro formation of triiodothyronine (T3) from T4 by liver microsomes was slightly decreased under basal conditions but similar after addition of glutathione. So the increased T4 half-life in deficient animals may be related to a decreased 5'-monodeiodase activity resulting from decreased glutathione availability. In deficient rats, the T3 serum level was increased, the T3 biological half-life was similar and the T3 distribution space was much decreased.

The daily food intake of a large dose of retinol (as palmitate) or retinoic acid (as all-trans retinoic acid) modifies numerous parameters of the thyroidal status in the rat. There were decreases of the serum total thyroxine (TT4) and triiodothyronine (TT3), and of the biological half-life of T4, while there were increases of the dialyzable fractions of T4 and T3 and of the apparent distribution space of T3. The possible causes of these changes are discussed.

24 hour fasting rats are anaesthetized and the small intestines are perfused in situ with a Tyrode solution at 37 degrees C, 1 ml/min., containing 0,5 to 15 g of glucose per liter. Larger amounts of glucose and water are absorbed by the intestine of vitamin A-deficient rats at all oncentrations of glucose. Intestines of meal fed rats absorbed more glucose than ad libitumnes. Plasma glucose and insulin levels are measured both before and during the perfusions everal higher values of hyperglycemia are noted in deficient rats which developed a particular lower insulinemia (these results are detailed in a further article).

We have studied the variations of the blood glucose and insulin concentrations of control and vitamin A-deficient rats after administration of glucose by various ways. The avitaminosis decreases the initial glycaemia and insulinaemia in fasting rats. It seems that the insulin release from the pancreas of the deficient rats is normal after a moderate treatment: for example after a single injection of glucose 0,5 g/kg in the carotide, or during the digestion of a mixed meal (rats trained to eat their day's food in a short time), or during an intestinal perfusion in vivo of weak concentrated glucose solutions (0,5 to 2 g/l). But after meal feeding a glucose rich diet (65 p. cent) or during intestinal perfusions of solutions with a higher glucose content (up to 15 g/l) the hyper-insulinaemia is fleeting in the deficient rats and its appeared highest hyperglycaemia in some perfused animals. The endocrine regulations of the vitamin A-deficient rats are considered in the discussion.

The total (TT3) and free serum triiodothyronine (fT3) and the distribution of a tracer dose of 125I-T3 were studied in rats on a vitamin A-deficient diet. After 6 weeks on the diet there was an increased serum T3 (TT3 and fT3). But after injection of 125I-T3 a smaller radioactivity was counted in kidney and liver of deficient animals, thus revealing a smaller transport of T3 into the target cells. So vitamin A-deficiency induces an original hormonal status responsible for the conflicting metabolic changes already described in deficient rats.