Retinol, circulating

As retinol circulates in plasma as a 1 1 1 complex with RBP and transthyretin, both of these hepatically produced proteins have been measured as an indicator of vitamin A status. RBP has been measured by radial immunodiffusion or nephelometry (see Chapter 20), but its circulating concentration may be limited by inadequate dietary protein, energy, or zinc, all of which are necessary for RBP synthesis. Another confounding factor in the assessment of vitamin A status is the effect of the APR. Both RBP and transthyretin... 

Centanni M, Maiani G, Parkes AB, N Diaye AM, Ferro-Luzzi A, Lazarus JH (1995) Thyroid homeostasis and retinol circulating complex relationships in a severe iodine-deficient area of Senegal. J Endocrinol Invest 18 608-612... 

Studies using computer-based compartmental modeling to analyze plasma retinol kinetics have shown that each molecule of retinol circulates through the plasma compartment several times before it is irreversibly degraded (see Tissue Retinoid Metabolism ). In a young man who consumed... 

A small but variable proportion of the carotenoids with one or two P-ionone rings (mainly P-carotene) are cleaved in the enterocytes to produce retinol (vitamin A). This process is very tightly controlled, so that too much vitamin A is not produced, although the control mechanism is not clear. Some cleavage of P-carotene can also occur in the liver, but this does not account for the turnover of P-carotene in the body. Small amounts of carotenoids are subject to enterohepatic circulation, but this does not account for losses. 

Dietary vitamin A is stored in the liver and secreted into the bloodstream when needed. The circulating retinol is taken up by target cells and oxidized in part to retinoic acid, which induces the synthesis of proteins through the direct control of gene expression. This type of action—gene activation—establishes vitamin A (in the form of its metabolite, retinoic acid) as a hormone, similar to the steroid hormones and the thyroid hormone. 

In another study (Moriel et al., 2002), 11 patients with mild essential hypertension were compared with 11 healthy subjects for water- and lipid-soluble antioxidants and the concentrations of nitric oxide derivatives in the plasma. A significant reduction in plasma lycopene was observed in the hypertensive patients compared to the normal subjects. Similar reductions in ascorbate, urate, and (3-carotene were also observed in this study. However, there were no differences in the nitrous oxide derivatives between the two groups. Hypertension and lymphatic circulation impairment are associated with liver cirrhosis. When patients with liver cirrhosis were compared to healthy matched controls, a significant reduction in serum lycopene, other carotenoid antioxidants, retinol, and oc-tocopherol were observed in the cirrhotic patients. Based on these observations, the authors recommend thorough screening for the antioxidants and improved diet in the... 

When vitamin A stores are adequate, the liver secretes retinol bound to retinol-binding protein (RBP) into the circulation to provide tissues with a constant supply of vitamin A. In the circulation, the retinol-RBP complex is found bound to another circulating protein of hepatic origin, transthyretin (TTR). TTR also binds thyroid hormone and consequently plays a role in the transport of both vitamin A and thyroid hormone. The molecular size of the retinol-RBP complex is quite small, and the formation of the... 

Stable isotopes of retinal and (3-carotene have also been employed to assess liver vitamin A stores in healthy individuals, and the best measure of vitamin A status (Furr et ah, 1989). The relative ratio of circulating isotopically labeled retinol is later assessed to estimate liver levels (Wang et ak, 2000 Hickenbottom et ah, 2002b) and without this technique, a liver biopsy would be necessary to estimate liver levels. 

Within the enterocyte, retinol is bound to cellular retinol binding protein (CRBP 11) and is esterified by lecithin retinol acyltransferase (LRAT), which uses phosphatidylcholine as the fatty acid donor, mainly yielding retinyl palmitate, although small amounts of stearate and oleate are also formed. At unphysiologically high levels of retinol, when CRBP 11 is saturated, acyl coenzyme A (CoA) retinol acyltransferase (ARAT) esterifies the free retinol that accumulates in intracellular membranes. Then the retinyl esters enter the lymphatic circulation and then the bloodstream (in chylomicrons), together with dietary lipid and carotenoids (Norum et al., 1986 Olson, 1986 Blomhoff et al., 1991 Green et al., 1993 Harrison and Hussain, 2001). 

A small proportion of dietary retinol is oxidized to retuioic acid, which is absorbed into the portal circulation and bound to serum albumin. Some retinyl esters are also transferred into the portal circulation. Patients with abeta-lipoproteinemia, who are unable to synthesize chylomicrons, can nevertheless maintain adequate vitamin A status if they are provided with relatively high intakes of retinol. 

Release of retinol from stellate cells into the circulation may occur either directly, as free retinol bound to RBP, or indirectly as a result of the transfer of retinol from stellate cells to hepatocytes. The release of retinol from stores is impaired in iron deficiency, as is the absorption of dietary vitamin A (fang et al., 2000). 

A variety of other tissues synthesize RBP this provides a mechanism for return to the liver of retinol in excess of requirements that has heen taken up from chylomicrons hy the action of Upoprotein lipase. Because these tissues do not synthesize transthyretin, the hinding of holo-RBP to transthyretin must occur in the circulation after release. 

Protein-energy malnutrition results in functional vitamin A deficiency, with very low circulating levels of the vitamin and development of clinical signs of xerophthalmia (Section 2.4). The condition is unresponsive to the administration of vitamin A and often occurs despite adequate liver reserves of retinol. The problem is one of impaired synthesis of RBP in the liver and hence a... 

They are also important in intracellular trafficking and transport of retinoids. CRBP(II) interacts direcdy with the enterocyte membrane retinol transporter, and CRBP(I) with the cell surface RBP receptor, thus permitting direct uptake and accumulation of retinol from the intestinal lumen and circulation respectively. CRBP(l) is present in large amounts in cells that synthesize and... 

Retinoic acid may either enter the target cell from the circulation or may be formed intraceUularly by oxidation of retinol. A number of tissues - but not muscle, kidneys, small intestines, liver, lungs, or spleen - have a cellular retinoic acid binding protein (CRABP) that is distinct from CRBP. Testis and... 

The Relative Dose Response (RDR) Test The RDR test is a test of the ahUity of a dose of vitamin A to raise the plasma concentration of retinol several hours later, after chylomicrons have heen cleared from the circulation. What is being tested is the ahUity of the liver to release retinol into the circulation. In subjects who are retinol deficient, a test dose will produce a large increase in plasma retinol, because of the accumulation of apo-RBP in the liver in deficiency (Section 2.2.3). In those whose problem is due to lack of RBP, then little of the dose will be released into the circulation. An RDR greater than 20% indicates depletion of liver reserves of retinol to less than 70 /rmol per kg (Underwood, 1990). 

As the intake of vitamin A increases, there is an increase in the excretion of metabolites in bile, once adequate liver reserves have been established. However, the biliary excretion of retinol metabolites reaches a plateau at relatively low levels, and it seems likely that this explains the relatively low toxic threshold (Olson, 1986). Vitamin A intoxication is associated with the appearance of both retinol and retinyl esters bound to albumin and in plasma lipoproteins, which can be taken up by tissues in an uncontrolled manner the amount of circulating retinol bound to RBP does not increase. Retinol has a membrane lytic action it was noted in Section 2.2.2.3 that one of the functions of RBP binding seems to be to protect tissues against retinol, as well as to protect retinol against oxidation (Meeks et al., 1981). 

Vitamin A is stored in the stellate cells of the liver in the form of retiny I esters. With mobilization of the vitamin, the relinyl ester is converted to retinol and released into the bloodstream as a complex with RM The complex contains one molecule of retinol and one molecule of protein. RBP is not released into the circulation unless it contains a molecule of retinol. Various cells of the body contain RBP receptors. The RBP receptor is a membrane-bound protein. It is required for the uptake of the vitamin. Apparently RBP does not enter the cell when it discharges retinol. The following experiment, which involved the epithelial cells of bovine eyes, illustrates the role of RBP Vitamin A is very important for the health of many epithelial cells, including tho.se of the eyes. The cells were maintained in culture in a petri dish- Retinol was added to the cells in the form of a retinol-RBP complex... 

Thyroid hormones have a lengthy life-span in the bloodstream — several days — probably because they are bound to proteins in the circulation. More than of T4 and T3 is bound to plasma proteins. These prolerns arc thyroid hormone-binding protein, transthyretin, and albumin. Most of the hormone is carded by thyroid hormone-binding protein. Transthyretin (from thyroid and retinol) occurs in a Irl complex with retinol-binding protein In the bloodstream. This complex serves to prevent the loss of retinol-binding protein, which is a small protein, in the urine. Transthyretin has also been called prealbumin, it binds T4 and not TJ,... 

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