Retinol deficiency

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). 

Pirie A, Werb Z, and Burleigh M (1975) Collagenase and other proteinases in the cornea of the retinol deficient rat. British Journal of Nutrition 34, 297-309. 

Vitamin A Both vitamin A (= retinol) and A2 (= 3-dehydroreti-nol) occur in nature. Like their derivatives, they are classed under the umbrella term axerophtol. The major provitamin is p-carotin. Vitamin A is stored as a lipoglycoprotein complex in the fat-storing cells of the liver. It is released when necessary by being coupled with a retinol-binding protein (RBP) and is then transported to the cells which require vitamin A. In the case of zinc deficiency the rate of RBP synthesis is markedly increased, and as a result serum retinol concentration is reduced. Retinol deficiency can be compensated by zinc substitution. The daily requirement is approx. 1 mg. (7, 36)... 

Retinoic acid is required for the development of goblet mucous cells. A deficiency results in basal cell proliferation with increased keratini-zation of the epithelial structures. Mucus is one of the essential physical barriers (part of innate immunity) that prevents pathogens from entering the body. Therefore, a retinol deficiency increases the risk of infection. 

A deficiency causes night blindness, which is considered an early symptom of retinol deficiency. Night blindness refers to decreased ability to see in very dim light because there is an inadequate amount of retinal in the eye to fuUy "stock" the rods with functional rhodopsin. There is some evidence that as retinol levels in the liver decrease, the equilibrium favors the movement of retinol from the eye back to the liver. 

Because retinol deficiency results in keratini-zation of epithelial tissue, at one time retinol was recommended for skin conditions including acne. There is no clinical evidencethat retinol is effective for skin conditions. Now that it is realized that the active form is retinoic acid, the focus has been on developing pharmacologically active compounds based on this structure. These are divided into treatment of three groups (i) acne, (2) the autoimmune disease psoriasis, and malignancies. 

Ravi Kumar, S., Narayan, B., and Vallikannan, B. (2008). Fucoxanthin restrains oxidative stress induced by retinol deficiency through modulation of Na+ Ka+-ATPase and antioxidant enzyme activities in rats. Eur. J. Nutr. 47, 432-441. 

Sangeetha, R., Bhaskar, N., and Baskaran, V. (2009). Comparative effects of P-carotene and fucoxanthin on retinol deficiency induced oxidative stress in rats. Mol. Cell. Biochem. 331, 59-67. 

The tissue distribution and levels of RBP in normal and in retinol-deficient rats were measured in order to explore the role of different tissues in the metabolism of RBP (J. E. Smith et al., 1975). The tissues examined included liver, kidney, fat, muscle, brain, eye, salivary gland, thymus, lung, heart, intestine, spleen, adrenal, testes, thyroid, and red blood cells. The RBP levels were low or very low in tissues other than liver, kidney, and serum and varied from 12 p.g/g of tissue for normal spleen to an undectable level in red blood cells. Much of the RBP in the tissues with low levels was most likely due to residual serum in the samples. In general, except for liver, RBP levels were lower in tissues from retinol-deficient rats than in those fixim normal rats. In normal rats, the liver, kidney, and serum levels were 30 4 (mean SEM), 151 22, and 44 3 p.g/g, respectively. In retinol-deficient rats, the liver RBP level was about three times the normal level whereas the kidney and serum levels were about one-fifth the normal values. It was suggested that die levels of RBP in normal as compared to deficient liver, serum, and kidney appear to reflect the relative rates of RBP secretion and turnover (see later discussion). 

One factor that exerts control over RBP secretion from the liver is the nutritional vitamin A (retinol) status of the animal. It is now well established that retinol deficiency specifically blocks the secretion of RBP from the liver so that... 

Extensive studies conducted during the past decade have demonstrated that the availability of retinol to the liver cell plays a critical role in the control of RBP secretion from the cell. The effects of retinol depletion and of retinol repletion are illustrated in Fig. 4. In the retinol-deficient state, the secretion of RBP from the liver is blocked, resulting in the accumulation of an enlarged pool of apo-RBP in the liver, and a concomitant decline in serum RBP level (Muto et al., 1972 J. E. Smith et al., 1973a). Conversely, repletion of retinol-deficient rats with retinol stimulates the rapid secretion of RBP from the expanded liver pool into the plasma. 

Repletion of retinol-deficient rats can also be effectively achieved by the intravenous injection of retinol dispersed in a 20% Tween 40 solution (Smith et al., 1980 Fig. 4). Such an injection produces a rapid, dose-related increase in the serum concentration of RBP. The changes in serum RBP levels seen after the injection of retinol in a 20% Tween 40 solution closely resembled those previously seen after the injection of vitamin A (retinyl esters) in association with lymph chylomicrons. However, the amount of retinol required to stimulate the secretion of a given amount of RBP from the liver was about two to three times that required when retinol (retinyl esters) was injected in chylomicrons. As discussed by Smith et al. (1980), this quantitative difference is probably due to differences in the tissue distribution pattern of retinol when injected in the Tween 40 solution, compared to its administration in the form of chylomicrons. 

Since RBP synthesis rate remains normal in retinol-deficient rats, whereas RBP secretion from the liver is blocked in these animals, this study suggests that the RBP degradation rate in the liver must be increased sufficiently in the deficient rats to maintain the elevated steady-state levels of RBP seen in their livers. No information is available about the mechanisms that may be involved in RBP catabolism in the liver or about their possible regulation. 

The roles of various subcellular organelles and structures in the hepatic metabolism and secretion of RBP have been studied with both normal and retinol-deficient rats. These studies have employed assays for a variety of marker enzymes and other constituents. After differential centrifugation of liver homogenates, 79 1% of the RBP was found associated with the liver microsomes (Harrison et al., 1979). Similar proportions of total liver RBP were found in the microsomal fractions of livers from both normal and retinol-deficient rats (J. E. Smith et al., 1975). Further subfractionation of the microsomal fraction showed that RBP was particularly enriched in the rough microsomal fraction (3.8 0.5-fold over the homogenate), which contained 49 4% of the liver microsomal RBP (Smith and Goodman, 1979). RBP was also enriched in the smooth microsomal fraction (3.2 0.2-fold over the homogenate). 

The effects of colchicine on RBP secretion and metabolism by the liver were explored by Smith et al. (1980). Colchicine treatment of retinol-deficient rats markedly inhibited the retinol-stimulated secretion of RBP from the liver into the serum. The inhibition of RBP secretion was quantitatively quite similar to the inhibition of very low-density lipoprotein secretion by colchicine seen in parallel experiments. In contrast, colchicine did not affect the overall rate of protein synthesis within the liver. The inhibition of RBP secretion by colchicine suggests that the microtubules play a role in RBP secretion. 

When retinol-deficient rats were first treated with colchicine and then injected with retinol to stimulate RBP secretion, the RBP content of a Golgi-rich fraction from liver increased markedly, to a maximum of 34% of the total liver RBP. The level of TTR in the Golgi was not influenced by retinol injection. 

Taken together, these studies are consistent with the conclusion that the Golgi apparatus, Golgi-derived secretory vesicles, and microtubules are involved in the normal pathway of RBP secretion in the liver cell. Thus these studies suggest that the RBP secretory process involves the same subcellular organelles and pathways previously shown to be involved in the secretion of other serum proteins such as albumin (Redman et al., 1975). These data also suggest that the block in RBP secretion found in retinol deficiency occurs at a site before the RBP molecule reaches the major portion of the Golgi apparatus. 

As discussed above, in retinol deficiency newly synthesized apo-RBP accumulates in the hepatic endoplasmic reticulum (microsomal fraction), whereas the secretion of serum albumin, TTR, and other plasma proteins appears to continue at a normal rate. The mechanisms responsible for the selective retention of RBP in the endoplasmic reticulum and for the specific stimulation of RBP secretion when retinol is made available, are not known. 

In addition to retinol deficiency, a number of factors may affect the extent to which retinol is available, at the appropriate anatomic locus within the liver cell, for complex formation with apo-RBP. In view of the critical role played by retinol in influencing the rate of RBP secretion, these factors can be considered as potentially significant with regard to the regulation of RBP secretion. Thus, these factors warrant exploration and delineation. 

Kaul S, Krishnakantha TP. Influence of retinol deficiency and curcumin/turmeric feeding on tissue microsomal membrane lipid peroxidation and fatty acids in rats. Mol Cell Biochem 1997 175 43 8. 

Kaul S, Krishnakanth TP. Effect of retinol deficiency and curcumin or turmeric feeding on brain Na(+)-K+ adenosine triphosphatase activity. Mol Cell Biochem 1994 137 101-107. 

Venkataswamy G, Glover J, Cobby M, Pirie A (1977) Retinol-binding protein in serum of xeropthalmic, malnourished children before and after treatment at a nutrition center. Amer J Clin Nutr 30 1968-1973 54 Dixon JL, Goodman DS (1987) Studies on the metabolism of retinol-binding protein by primary hepatocytes from retinol-deficient rats. J Cell Physiol 130 14-20... 

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