Plasma Retinol Binding Protein RBP

Retinol is released from the liver bound to an a-globulin, retinol binding protein (RBP); this serves to maintain the vitamin in aqueous solution, protects it against oxidation, and also delivers the vitamin to target tissues. RBP binds 1 mol of retinol per mol of protein.

RBP forms a 1:1 complex with the tetrameric thyroxine-binding prealbumin, transthyretin. This is important to prevent urinary loss of retinol bound to the relatively small RBP (Mr 21,000), which would be filtered by the glomerulus; transthyretin has an Mr of 54,000; hence, the complex will not normally be filtered. However, moderate renal damage, or the increased permeability of the glomerulus in infection, may result in considerable loss of vitamin A bound to RBP-transthyretin.

The transthyretin tetramer could theoretically bind 2 mol of holo-RBP, but does not, because holo-RBP is limiting. In vitamin A deficiency, the ratio of RBP:transthyretin falls, indicating that although binding to transthyretin is essential for secretion ofholo-RBP from the liver, vitamin Ais not essential for secretion of transthyretin. Other tissues secrete holo-RBP, but not transthyretin; it is assumed that this binds to transthyretin in the circulation.

In the liver, the apo-RBP-transthyretin complex is formed in the rough endoplasmic reticulum and then migrates through the smooth endoplasmic reticulum to the Golgi on binding retinol. Calnexin, an integral membrane protein, coprecipitates with the apo-RBP-transthyretin complex, suggesting that migration of the apo-protein into the Golgi is prevented by membrane binding. Binding of retinol to the complex displaces calnexin, so that the holo-RBP-transthyretin complex is now free to migrate to the Golgi for secretion (Bellovino etal., 1996).

Metabolites ofpolychlorinated biphenyls bind to the thyroxine binding site of transthyretin and, in doing so, impair the binding of RBP. As a result of this, there is free RBP-bound retinol in plasma, which is filtered at the glomerulus and hence lost in the urine. This may account for the vitamin A depleting action of polychlorinated biphenyls (Brouwer and van den Berg, 1986).

RBP is relatively rich in aromatic amino acids, which create a deep hy-drophobic pocket that is specific for the f-ionone ring, polyene side chain, and polar end group. In addition to all- trans-retinol, RBP binds retinaldehyde, retinoic acid, and 13-ds-retinol, but not retinyl esters or f -carotene. RBP shows considerable structural homology with f -lactoglobulin from milk and other binding proteins for lipophilic compounds. p -Lactoglobulin also binds retinol and may be important in the absorption of the vitamin in young animals.

Cell surface receptors in target tissues take up retinol from the RBP-transthyretin complex, esterifying it externally, then transferring free retinol by esterase activity onto an intracellular RBP. Part of the function of the receptor is to catalyze a conformational change in RBP so that the retinol held in the hydrophobic pocket can be released. There is no endocytosis of the RBP-transthyretin complex.

The cell surface receptors also remove the carboxy terminal arginine residue from RBP, thus inactivating it by reducing its affinity for both transthyretin and retinol. As a result, apo-RBP is filtered at the glomerulus. Some may be lost in the urine, but most is resorbed in the proximal renal tubules and is then catabolized by lysosomal hydrolases. This seems to be the main route for catabolism of RBP; the apo-protein is not recycled (Peterson et al., 1974).

During the development of vitamin A deficiency in experimental animals, the plasma concentration of RBP falls, while the liver content rises. The administration of retinol to deficient animals results in a considerable release ofholo-RBP from the liver. This is a rapid effect on the release of preformed apo-RBP in response to the availability of retinol, rather than an increase in the synthesis of the protein. There is no evidence that retinol controls the synthesis of RBP (Soprano et al., 1982). This provides the basis of the relative dose response (RDR) test for liver stores of vitamin A (Section 2.4.1.3); administration of a test dose of retinol gives a considerably greater increase in plasma retinol, bound to RBP, in deficient subjects than in those with adequate liver reserves, because of the accumulation of apo-RBP in the liver.

As well as protecting retinol against oxidation, the binding of retinol to RBP may also serve to protect the body against the general membrane-seeking and potentially membrane lytic effects of retinol. In tissue culture, the addition of retinol nonspecifically bound to albumin results in lysosomal membrane damage and the release of lysosomal hydrolases. Retinol bound to RBP does not have this effect, suggesting that the high affinity of RBP for retinol protects tissues against nonspecific uptake of the vitamin. Vitamin A toxicity occurs when there is such an excess that RBP is saturated and retinol circulates bound to other proteins and as esters in plasma lipoproteins (Meeks et al., 1981).

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 seriously impaired ability to release retinol from liver stores. During rehabilitation of protein-energy malnourished children, there is a rapid increase in plasma retinol as a result of increased synthesis of RBP. Deficiency of zinc also impairs synthesis of RBP.

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