RBP Metabolism

RBP is synthesized and secreted by the liver and circulates in plasma mainly as a protein-protein complex with TTR. Normally, RBP is secreted almost entirely as the holoprotein, containing a molecule of bound retinol. TTR is also produced 

Retinol is delivered to target tissues by holo-RBP, possibly by the very small amount of holo-RBP normally present in the free uncomplexed state. Etelivery of retinol to extrahepatic tissues may involve specific cell-surface receptors for RBP. The apo-RBP that results after delivery of retinol probably has a reduced affinity for TTR and is thus selectively enriched in the free RBP fraction. 

Free uncomplexed RBP is small enough to be filtered by the renal glomeruli, whereas TTR and the RBP-TTR complex are not. Although very little RBP is normally present in the free state, the rates of glomerular filtration and renal metabolism of RBP are sufficiently large enough to constitute the major pathway of RBP catabolism. Patients with severe chronic renal disease show a reduced metabolic clearance rate and an elevated plasma concentration of RBP, with normal levels of TTR. 

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RBP has been found in relatively large amounts in the urine from patients with tubular proteinuria (Peterson and Berggard, 1971). Much is known about urinary protein excretion of Japanese patients with chronic cadmium poisoning (Kanai-er al., 1972a,b). These patients manifest tubular proteinuria and the excretion of considerable amounts of low-molecular-weight proteins, including RBP. The urinary excretion of RBP has been induced in a rabbit (Muto et al., 1976) and in a rhesus monkey (Nomiyama et al., 1981) by chronic poisoning with cadmium. Studies of the role of the kidney in RBP metabolism have also been carried out in rats with various kinds of experimentally induced renal lesions (Peterson et al., 1974). These various reported observations are all consistent with the above postulated role of the kidney in RBP metabolism. 

Figure 5 is a diagram that summarizes information available about retinol and RBP metabolism in the hepatocyte. 

While much has been learned from whole-animal studies about the regulation of RBP metabolism, the interpretation of these results is sometimes clouded owing to the interplay between organs. To avoid this problem, studies have been conducted in vitro with isolated liver cells in culture. 

Zinc represents another nutrient whose nutritional status may influence plasma vitamin A and RBP levels in malnourished children. Interrelationships between zinc and vitamin A have been reviewed in detail by Solomons and Russell (1980) and by Smith (1980), and are discussed and summarized in Chapter 6, Vol. 1. Studies in experimental animals have shown that zinc deficiency is associated with low plasma vitamin A and RBP levels. It has been suggested that this may be due in part to impaired hepatic synthesis of RBP (Smith et al., 1974). This effect on RBP production has not been thought to be in any way specific for RBP rather hepatic synthesis of plasma proteins in general appears to be impaired in zinc deficiency, with RBP being one of the hepatic proteins most sensitive to this deficiency. The main effect of zinc deficiency on vitamin A and RBP metabolism appears, however, to be secondary to the depressed food intake... 

FIGURE 3.2.2 Metabolic pathways of carotenoids such as p-carotene. CM = chylomicrons. VLDL = very low-density lipoproteins. LDL = low-density lipoproteins. HDL = high-density lipoproteins. BCO = p-carotene 15,15 -oxygenase. BCO2 = p-carotene 9, 10 -oxygenase. LPL = lipoprotein lipase. RBP = retinol binding protein. SR-BI = scavenger receptor class B, type I. 

The retinoids involved specifically in vision do not relate to the same chemical receptors as those found in the nutrition aspects of pharmacology. There is a different set of chemical receptors involved in the transport of retinol from the liver to the RPE cells of the retina. These receptors are found on the surface of the RPE cells and are specific for the retinoid binding proteins (RBP s) that transport the retinoids to the RPE. These RBP s play a unique role in the chromophore forming process that is not shared with the transport of retinol for purposes of metabolism and growth. Machlin says there are as many as 50,000 RBP receptor sites on the exposed surface of each RPE cell212. 

The retinyl esters are incorporated into chylomicrons, which in turn enter the lymph. Once in the general circula-tion. chylomicrons arc converted into chylomicron remnants, which arc cleared primarily by the liver. As the c.stcrs enter the hepalocytes. they are hydrolyzed. In the endoplasmic reticulum, the retinol is bound to retinol-binding protein (RBP). This cotnplex is released into the blood or transferred to liver stellate cells fur storage. Within the stellate cells, the retinol is bound to CRBP(I) and e.stcnTicd for storage by ARAT and LRAT. Stellate cells contain up to 95% of the liver vitamin A. stores. The RBP-retinol complex released into the general circulation from hepalocytes or stellate cells, in turn, is bound to transthyretin (TTR), which protects retinol from metabolism and renal excretion. ... 

Fig. 2. Tissue distribution and metabolism of retinoids in fish. Dietary carotenoids (e.g. /3-carotene (/3C)) and retinyl esters (e.g. retinyl palmitate (RP)) are converted into retinol (Rol) in the lumen of the gut. Retinol is then re-esterified and packaged into chylomicrons and transported to the portal circulation. When required elsewhere, stored retinyl esters (e.g. RP) in the liver are hydrolyzed to retinol and transported in the blood bound to the retinol-binding protein (RBP). Retinol is converted in target tissues to RA, RP or retinal (Ral). RA may exert its effects locally, or be returned to the circulation and transported throughout the body bound to albumin. RA can then be sequestered in other tissues.

FIG. 1. Initial conceptual model for vitamin A metabolism. SI, small intestine RE, retinyl esters ROH, retinol RBP, retinol-binding protein. 

The moderate depression in carrier proteins could be the consequence of either an increased rate of catabolism consequential to an elevated metabolic rate or a decreased rate of hepatic synthesis and mobilization. Although early animal studies gave inconsistent results (Johnson and Baumann, 1948 Anderson et aL, 1964), the weight of evidence suggests that an increased metabolic rate significantly increases the rate of vitamin A utilization. The observations in humans of depressed circulating levels of vitamin A and its carrier proteins in febrile conditions (Arroyave and Calcano, 1979) are in accord with this hypothesis. An increased utilization of retinol would increase the turnover of RBP also, since apo-RBP normally has a short transient time in the circulation. 

Hydrolysis of retinyl esters occurs in the liver both during the hepatic uptake of dietary vitamin A and during the mobilization of retinol from its stores in the liver. The hydrolysis of chylomicron retinyl esters that occurs during hepatic uptake has been discussed above. In addition, retinyl ester hydrolysis must precede the mobilization of retinol from hepatic stores of retinyl ester since retinol is mobilized in the form of the unesterified alcohol (retinol) bound to RBP. Accordingly, it is clear that the enzymatic hydrolysis of retinyl esters in liver represents an important process in the overall metabolism of retinol in the body. 

The retinol transport system provides an interesting model for the study of protein-protein and protein-retinoid interactions and of the characteristics and metabolic regulation of a specific binding and transport system. The aim of this chapter is to summarize the information available about this transport system, including information about the structure and chemistry, biochemistry, and metabolism of RBP, and about related clinical phenomena. Brief comments are also... 

Fig. 3. Schematic summary of the metabolism of RBP. See text for description and discussion.

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