Distance bi-chiku rar

In conclusion, vitamin A metabolites act as intracellular ligands on identified receptors and other cellular targets. Unknown or controversial steps persist such as: what are the sensor mechanisms promoting the liberation of stocks of retinol from the liver, are the oxidised metabolites of RA really inactive, are there mechanisms specifically responsible of isomerisation of RA, are there specific cellular actions of the RA isomers, are there hormonal controls of RA signalling, etc?

Keeping these interrogations in mind, we will present the known interactions of vitamin A and metabolites with endocrine tissues and hormones action. There are arguments for a role of retinoids in the development and function of the hypothalamus, the pituitary and the peripheral glands they act upon.

In vivo studies also show modifications of hypothalamo—pituitary—peripheral gland axes upon retinoid deprivation or treatment 31 , 32 , 33 , 34 , 35 , RA does not seem to be involved in thyroid organogenesis Conversely, RA appears involved in maintaining a developed thyroid cell phenotype both in animals and humans.

In animals, vitamin A deficiency causes thyroid hypertrophy with a reduction of iodine uptake, of thyroglobulin and of thyroid hormones synthesis 38 and older publications within.

Combined iodine and vitamin A-deficient diets produce greater impairments in thyroid metabolism than either isolated iodine or vitamin A-deficient diets. In children with moderate vitamin A deficiency, TSH concentrations, thyroid volume and total T4 are increased There are interactions between vitamin A and iodine metabolism as indicated by observational and interventional studies.

In iodide-deficient children, vitamin A increases TSH stimulation and thyroid size but reduces risk of hypothyroidism 31 , In these children, vitamin A supplementation improves iodide efficiency 31 , Thus, various works investigated the actions of RA on thyrocytes mainly expression and function of key proteins.

Retinyl palmitate administration decreases thyroid gland size and serum thyroid hormones and conversely increases thyroidal iodine uptake and hepatic conversion of T4 to T3 in rats Interestingly, a low dose of atRA decreased iodine uptake, whereas the same dose of cis RA increased iodine uptake RA isoforms may thus have different consequences on thyrocyte functions.

TSH-induced thyroid hormones synthesis requires the incorporation of iodide into the thyrocytes via the sodium—iodide symporter NIS , its transport through the cell with pendrin to thyroglobulin Tg in the lumen.

Various steps in this process depend on RA with noticeable differences related to the different cell models used complicating the description of the physiological role of RA. As cis RA does not bind efficiently to RAR or RXR, this suggests either different cellular targets for these two retinoids or a critical role for the inter isomer conversion.

The main recent reason for the interest about the role of RA in the thyroid is probably its potential therapeutic use in thyroid cancer. The rational for this interest is precisely the potential ability of RA isoforms to sustain cell differentiation or to reverse cell dedifferentiation in various models of cancer. With regards to a potential use to eradicate cancer cells with I, NIS was particularly investigated. More importantly, an increase of iodide uptake was described in human thyroid cancer 43 , Thus, the use of RA in thyroid through the increased expression of NIS to increase I uptake has been under careful investigation in human cancers 45 , 46 , 47 , Unfortunately, different studies did not report a clear usefulness for such a treatment in thyroid cancer Though, for a similar expected action on NIS, RA is under consideration for the treatment of breast cancer RA can also modulate the effects of thyroid hormones on target tissues.

Firstly, RA induces the expression of the thyroid hormone transporter, monocarboxylate transporter This is responsible for a crosstalk between RA and thyroid hormones signalling at least during critical steps of embryo brain development Secondly, although RAR and thyroid receptors do not seem to directly physically interact, they share some cofactors such as CART1 a de-repressor in the cytoplasm and NCoR2 a corepressor in the nucleus 53 , It is then likely that some form of competition occurs between the two ligands and their receptors.

Subsequent consequences would then depend on resulting gene trans-activations and trans-repressions. Lastly, there are interferences between thyroid and retinoid signalling. For instance, during a vitamin A-deficient diet or in aged rats, retinoid and thyroid nuclear receptor expressions decrease.

This can be corrected by either thyroid hormone or RA treatments In humans, such a link is likely since a decreased expression of RAR occurs in mononuclear cells of hypothyroid patients Conversely, an increased concentration of retinol was seen in hypothyroidism. Currently, it is not known if a thyroid hormone replacement therapy restores RA signalling back to a status seen in euthyroidism. In conclusion, there are many levels where RA can interact with the physiology of hypothalamo—pituitary—thyroid axis including through vitamin A and iodine co-deficiency in low-income living conditions.

Unfortunately, the hopes raised by early work in thyroid cancers are probably dashed now because of the absence of clear usefulness. No information has been reported about a role of RA and calcitonin secretion by normal thyroid C cells.

In vitro , 9-cis RA decreases the release of calcitonin in the rat C cell line CA 57 , but no data are available about the spontaneous presence of 9-cis RA in C cells. For instance, chronic treatment of young rats by RA increases basal corticosterone concentration However, most of the recent literature refers to its possible use or role in pituitary or adrenal tumours.

Furthermore, RA is localised in some hypothalamic neurons although it is not yet known whether these neurons regulate the HPA axis Retinaldehyde dehydrogenase enzymes are also localised in the hypothalamus Altogether these data strongly supports a role of RA in regulating hypothalamic functions.

Secondly, RA could act on the secretion of corticotrophs, but there are apparently conflicting data. No in vitro data are available about RA and normal corticotrophs. An apparently opposite effect has been shown in tumoural cells as RA reduces growth and secretion of AtT20 cells 61 possibly through bone morphogenic protein 4 action 61 , 62 , 63 , Ectopic ACTH secretion may also be affected by retinoids. Indeed, the nuclear co-repressor SMRT is over-expressed in ACTH-secreting thymic carcinoids suggesting that aberrant expression might be involved in the pathogenesis of tumoural cortisol resistance BMP are known modulators of different hormonal systems including the adrenal.

Whether reactivating BMP signalling in adrenocortical tumour tissues by therapeutic retinoids is yet unknown Finally, a meta-analysis of adrenocortical tumour genomics data also revealed a putative role of RA signalling Lastly, part of the interaction between vitamin A and glucocorticoid action may occur downstream of adrenal hormone production as vitamin A and glucocorticoid receptors may interact directly or indirectly. As a consequence, RA is for instance able to decrease glucocorticoid receptor expression and modify glucocorticoid signalling in a neuronal model 23 , 70 , This increase, as well as the associated increased HPA axis activity, is normalised by RA administration RA is a critical factor for the formation of the gonads in man and one of the major consequences of vitamin A deficiency apart from blindness is infertility 35 , The role of RA in the production of gonadic hormones of developed gonads appears less important although RA stimulates steroid hormone synthesis.

It has been suggested that there is an interesting interplay between RA and oestrogen signalling in breast cancer cells particularly with opposite actions on cell proliferation. Whether this is true in normal breast cells is yet unknown and putative preventive action of breast cancer is unknown. RA probably plays a role not only in the differentiation of somatotrophs through pit-1 transcription factor 79 but also in the expression of growth hormone-releasing hormone GH-RH receptors in somatotrophs as there is a RARE in the promoter of GH-RH receptor gene In pituitary tumours including somatotroph tumours, RA increases the expression of type 2 dopamine receptors; hence, a possible therapeutic use to control these tumours using routine dopaminergic drugs RA action has also been described in prolactin-secreting cells either normal or tumoural as demonstrated for corticotrophs.

RA receptor signalling is required in early pancreatic progenitor cells for pancreatic development It is also required for maintaining both beta-cell function and mass in the adult pancreas Hereafter are some of the main arguments developed in recent years 6 , RA restores an insulin-secreting function of vitamin A-deprived rats. Interestingly, the pancreas is one of the few if any others tissues where endogenous 9cisRA has been detected 17 , Furthermore, Raldh3 retinaldehyde dehydrogenase 3 is present in the pancreas and promotes the formation of cis RA from cis retinal In diabetic mice, Raldh3 expression is increased, and this is correlated with reduced insulin and increased glucagon secretions.

Thus, in the pancreas, unusual RA isomers may play a role in pancreatic function, but confirmation of these studies has to be obtained. Finally, we will not cover the very interesting topic of glucose and lipid metabolism here because many interesting studies and reviews detailed the relations of vitamin A, lipids and binding protein 91 , 92 , 93 , 94 , There are in vivo and in vitro arguments in animals reporting the effects of RA on renin or angiotensin production 96 , 97 , 98 , RA seems to play neither a remarkable role in adrenal medulla organogenesis nor function in adults.

In vitro , RA could initiate neuronal differentiation in PC12 cells eliciting the expression of a nerve growth factor receptor as well as tyrosine hydroxylase expression This is usually considered as a differentiating action on cells sharing a common origin with neurons. In adult rats, however, this effect disappears and adult erythropoiesis takes place. It is now known that vitamin A and RA and metabolites are involved in some glands development as well as functions in adults.

Indeed, one of the most critical roles of vitamin A in human health is its effect on thyroid function as simultaneous iodine and vitamin A deficiencies potentiate to affect thyroid function.

To achieve adequate intake of these micronutrients, among others, is indeed a challenge in developing countries. Similarly, the role of vitamin A and metabolites is certainly important in the regulation of the HPA axis although the endocrine consequences on the whole population is more difficult to assess. Thanks to a better understanding of vitamin A and RA metabolites mechanisms of action through their various receptors some interesting pathways in normal or tumoural endocrine tissues have been uncovered.

However, useful therapeutic use of agonists or antagonists of these pathways is not available yet. A use of retinoids in pituitary tumours especially corticotroph adenomas may be emerging. Well-tolerated, clinically available retinoids used for skin or hematologic diseases, renders clinical studies comparing other medical options readily possible.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. National Center for Biotechnology Information , U.

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