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Background: Inadequate retinoid status has often been described as occurring with aging. Moreover, subclinical hypothyroid status has also been evoked in the elderly. Several studies performed in animals have described the crucial incidence of age-related hypo-functioning of retinoid and thyroid signalling pathways, particularly in the brain., Objective: The aim of the present study was to clarify whether aging modifies retinoid and thyroid signalling in humans., Methods: Using real-time RT-PCR the relative amount of mRNA of the retinoid (RARalpha, RARgamma and RXRalpha) and thyroid (TRalpha and TRbeta) nuclear receptors in peripheral blood mononuclear cells (PBMC) of young (24-57 years old, n = 22) compared with elderly (69-90 years old, n = 24) healthy subjects was quantitated. Classical plasma parameters used to characterize the retinoid and thyroid status - retinol (ROH), retinol-binding protein (RBP), free triiodothyronine (FT3) and thyroxine (FT4), thyroid-stimulating hormone (TSH) and transthyretin (TTR) - were also assessed., Results: RARgamma expression was significantly decreased in elderly versus young subjects while no modification of the retinoid-related plasma parameters ROH and RBP were emphasized by aging. Concerning thyroid criteria, the elderly exhibited an increase in TSH concentration (+39%) without significant modifications of FT3 and FT4, which indicated an age-related sub-clinical hypothyroidism. Concurrently, the amount of TR mRNA (alpha as well as beta subtypes) was significantly decreased in the elderly., Conclusion: These data constitute the first evidence of an age-related hypo-activation of the retinoid and thyroid nuclear pathways in PBMC. Further study of the possible association between the expression of the retinoid and thyroid nuclear receptors and age-related cognitive alterations in humans would be interesting.

Recent studies have revealed that retinoids play an important role in the adult central nervous system and cognitive functions. Previous investigations in mice have shown that vitamin A deficiency (VAD) generates a hypo-expression of retinoic acid (RA, the active metabolite of vitamin A) receptors and of neurogranin (RC3, a neuronal protein involved in synaptic plasticity) and a concomitant selective behavioural impairment. Knowing that RC3 is both a triiodothyronine (T3) and a RA target gene, and in consideration of the relationships between the signalling pathways of retinoids and thyroid hormones, the involvement of T3 on RA signalling functionality in VAD was investigated. Thus, the effects of vitamin A depletion and subsequent administration with RA and/or T3 on the expression of RA nuclear receptors (RAR, RXR), T3 nuclear receptor (TR) and on RC3 in the brain were examined. Rats fed a vitamin A-deficient diet for 10 weeks exhibited a decreased expression of RAR, RXR and TR mRNA and of RC3 mRNA and proteins. RA administration to these vitamin A-deficient rats reversed only the RA hypo-signalling in the brain. Interestingly, T3 is able to restore its own brain signalling simultaneously with that of vitamin A and the hypo-expression of RC3. These results obtained in vivo revealed that one of the consequences of VAD is a dysfunction in the thyroid signalling pathway in the brain. This seems of crucial importance since the down regulation of RC3 observed in the depleted rats was corrected only by T3.

It has recently been shown that high-fat diets induce the expression of peroxisome proliferator-activated receptor (PPAR) with a concomitant decrease in expression of retinoic acid (RAR) and triiodothyronine (TR) receptors in rat liver. The authors have suggested that PPAR activation may be responsible for these modifications in nuclear receptor expression. With the aim of gaining further insight into a possible relationship between the patterns of expression of these receptors, we have examined, using a pharmacological model, the effect of a strong and specific PPAR activation induced by bezafibrate, a peroxisome proliferator agent. Activation of PPAR was evaluated by quantifying PPARalpha mRNA and acyl-CoA oxidase mRNA. The expression of RAR and TR was determined by assaying the binding properties of these nuclear receptors and by quantifying the mRNA level of RARbeta and TRalpha1,beta1 isoforms. After a 10 day treatment of young rats, induction of PPAR (PPARalpha mRNA was increased by 40% [P < 0.05 and acyl-CoA oxidase mRNA by 411% [P<0.001]) and a concomitant decrease of RAR and TR expression (Maximal Binding Capacity was decreased by 21 and 26%, respectively [P<0.05]) in the liver was observed. RXRalpha mRNA expression was unchanged by treatment. Cross-talk between RAR, TR and PPAR signalling pathways may be implicated in the new patterns of nuclear receptor expression observed. The decreased expression of RAR and TR reported here could provide a novel element for the understanding of the link between PPAR and tumorigenesis in rat liver.

It has recently been shown that high-fat diets induce the expression of peroxisome proliferator-activated receptor (PPAR) with a concomitant decrease in expression of retinoic acid (RAR) and triiodothyronine (TR) receptors in rat liver. The authors have suggested that PPAR activation may be responsible for these modifications in nuclear receptor expression. With the aim of gaining further insight into a possible relationship between the patterns of expression of these receptors, we have examined, using a pharmacological model, the effect of a strong and specific PPAR activation induced by bezafibrate, a peroxisome proliferator agent. Activation of PPAR was evaluated by quantifying PPAR alpha mRNA and acyl-CoA oxidase mRNA. The expression of RAR and TR was determined by assaying the binding properties of these nuclear receptors and by quantifying the mRNA level of RAR beta and TR alpha1,beta1 isoforms. After a 10 day treatment of young rats, induction of PPAR (PPAR alpha mRNA was increased by 40% [P< 0.05 and acyl-CoA oxidase mRNA by 411% [P<0.001]) and a concomitant decrease of RAR and TR expression (Maximal Binding Capacity was decreased by 21 and 26%, respectively [P<0.05]) in the liver was observed. RXR alpha mRNA expression was unchanged by treatment. Cross-talk between RAR, TR and PPAR signalling pathways may be implicated in the new patterns of nuclear receptor expression observed. The decreased expression of RAR and TR reported here could provide a novel element for the understanding of the link between PPAR and tumorigenesis in rat liver.

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.

The expression of nuclear receptors of retinoic acid (RAR) and triiodothyronine (TR) was analyzed in the liver of rats aged 2.5 (young), 6 (adult) and 24 (aged) months. In aged rats, decreased binding properties, binding capacity (Cmax) and affinity (Ka), of nuclear receptors were observed. This resulted, at least in part, from decreased transcription of receptor genes in that the amount of their mRNA also decreased. Moreover, the activity of malic enzyme (ME) and tissue transglutaminase (tTG), whose genes are TR and RAR responsive, respectively, was reduced in aged rats. These results are in agreement with the decreased binding capacity of these receptors. An inducer-related increase of RAR and TR expression was observed 24 h after a single dose of retinoic acid administration (5 mg/kg), while retinol administration (retinyl palmitate, 13 mg/kg) was without incidence on nuclear receptor expression in aged rats.

Aging is accompanied by troubles resulting from changes in hormonal and nutritional status. Therefore, the abundance of mRNA coding for triiodothyronine (TR) and retinoic acid (RA) nuclear receptors was studied in the brain of young, adult and aged (2.5, 6 and 24 months, respectively) rats. In the brain of aged rats, there was a lower abundance of TR and RAR mRNA and a lower activity of tissue transglutaminase (tTG), an enzyme the gene of which is a target for retinoids. Administration of RA in these rats restored TR and RAR mRNA and the activity of tTG in the brain. The importance of these observations to the function of the aged brain is discussed.

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.

It is known that alcohol induces disorders in the metabolism of retinoids and particularly in the biosynthetic pathways of retinoic acid (RA). Since RA has, along with other hormones and particularly triiodothyronine (T3), a physiological role in the adult brain, the effect of chronic exposure to alcohol on RA and T3 status was investigated. The amounts of RA receptor (RAR) and T3 receptor (TR) mRNAs were quantified and the activity of the 'tissue' transglutaminase (tTG; an RA-dependent enzyme) was assayed in the brain of mice following chronic ethanol consumption (CEC; 12% v/v for 6-10 months). Compared to controls, ethanol-treated mice exhibited increased amounts of RAR and TR mRNAs together with an increase in tTG activity. It is hypothesized that the enhanced cellular action of RA and T3 could play a role in the previously described brain damages induced by CEC.

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.

Chronic alcoholism induces perturbations of storage and metabolization of retinol and related compounds. After 6 months of ethanol consumption we have observed in mouse liver an increased expression of Tri-iodothyronine receptors (TR) while the expression of retinoic acid (RA) receptors (RAR) was unaffected. After 10 months of alcoholization the TR expression was strongly increased and the RAR expression was also increased. At this time the activity of aldehyde dehydrogenase and that of alcohol dehydrogenase, two enzymes involved in biosynthesis of RA from retinol, were similar in the liver of alcoholized and pair-fed mice. Thus it can be hypothesized that (i) the change of RAR expression was, at least in part, the result of a change of TR expression (result in agreement with previous data), (ii) the increased expression of RAR could induce apoptosis and subsequently liver necrosis.

Retinoic acid (RA) and triiodothyronine (T3) exert many of their actions by binding to specific nuclear receptors (respectively, RA receptor (RAR) and T3) receptor (TR) belonging to a 'superfamily' of receptors. Some heterologous regulation of these receptors has been shown, and in particular regulation of the maximum binding capacity of TR by either retinol or RA. Now, using hyperthyroidic rats as a model, the effect of RA on binding capacity and on the mRNA levels of TR and RAR was investigated. The results show that the benefit of vitamin A treatment for the hyperthyroidic state, which has been described for a long time, could be the result of a down-heteroregulation of TR by RA, the active metabolite of retinol.