Retinol release from liver

Hydrolysis of retinyl ester to retinol occurs in the lumen of the small intestine from where it is absorbed with the aid of bile salts, esterified to form retinyl ester and then released into lymph where it is incorporated into chylomicrons. The action of lipoprotein lipase converts chylomicrons to remnants and the retinyl ester remains in the remnants to be taken up by the Uver, where it is stored as the ester until required. On release from the liver, it is transported in blood bound to retinal binding-protein. 

In the body retinol can also be made from the vitamin precursor carotene. Vegetables like carrots, broccoli, spinach and sweet potatoes are rich sources of carotene. Conversion to retinol can take place in the intestine after which retinyl esters are formed by esterifying retinol to long chain fats. These are then absorbed into chylomicrons. Some of the absorbed vitamin A is transported by chylomicrons to extra-hepatic tissues but most goes to the liver where the vitamin is stored as retinyl palmitate in stellate cells. Vitamin A is released from the liver coupled to the retinol-binding protein in plasma. 

Transport to the liver Retinol esters present in the diet are hydrolyzed in the intestinal mucosa, releasing retinol and free fatty acids (Figure 28.19). Retinol derived from esters and from the cleavage and reduction of carotenes is reesterified to long-chain fatty acids in the intestinal mucosa and secreted as a component of chylomicrons into the lymphatic system (see Figure 28.19). Retinol esters contained in chylomicrons are taken up by, and stored in, the liver. 

Release from the liver When needed, retinol is released from fie liver and transported to extrahepatic tissues by the plasma retax -binding protein (RBP). The retinol-RBP complex attaches to spe cific receptors on the surface of the cells of peripheral tissues, permitting retinol to enter. Many tissues contain a cellular letaiol-binding protein that carries retinol to sites in the nucleus where the vitamin acts in a manner analogous to steroid hormones. 

Free retinol is released from the liver as a 1 1 complex of retinol with the 21-kDa retinol-binding protein.k l This protein is normally almost saturated with retinol and is bound to another serum protein, the 127-residue transthyretin (prealburnin).m/n Some of the retinol is oxidized to retinoic acid. 

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. 

Retinol is nearly always present in the food in the form of esters which are hydrolysed in the lumen of the intestine. The retinol released is quite readily absorbed into the mucosal cells where it is re-esterified, chiefly with palmitic acid. The retinyl esters are then transported via the lymphatic system into the portal circulation from which they are removed and stored in the liver. Release of the vitamin from the liver depends on the production by the liver of a special retinolbinding protein (RBP). Production of the retinol-binding protein may be disturbed in diseases of the liver or kidneys or in protein/energy malnutrition. In such circumstances retinol cannot be mobilized from the stores and a secondary deficiency may result. Thus it can be seen that the level of retinol in the general circulation is normally highly regulated and is more or less independent of the body s reserves. 

Liver Storage and Release of Retinol Tissues can take up retinyl esters from chylomicrons, but most is left in the chylomicron remnants that are taken up into the liver by endocytosis. The retinyl esters are hydrolyzed at the hepatocyte cell membrane, and free retinol is transferred to the rough endoplasmic reticulum, where it binds to apo-RBP. Holo-RBP then migrates through the smooth endoplasmic reticulum to the Golgi and is secreted as a 1 1 complex with the thyroid hormone binding protein, transthyretin (Section 2.2.3). 

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. 

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 of holo-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 RB P (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. 

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). 

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. ... 

During absorption some /3-carotene is also converted to retinoid (Dimitrov et al, 1988 Olson, 1989 van Vliet et al, 1992 Scita et al, 1993) and transferred via a plasma chylomicron (renmant) retinyl ester compartment to a liver retinyl ester compartment. From here it is released in a plasma retinol-binding protein-retinol (RBP-ROH) compartment for transfer to target tissues. Eventually it is lost irreversibly from the RBP-ROH compart-... 

Zinc deficiency accompanied by a depression in plasma retinol has been noted in several studies. Some investigators have reported an increased liver vitamin A in several species of zinc-deficient animals (Stevenson and Earle, 1956 Saraswat and Arora, 1972 J. C. Smith et aL, 1973, 1976 Brown et aL, 1976 Jacobs et al., 1978 Carney et aL, 1976). There are also reports in humans in an association between lowered zinc, retinol, and RBP (Jacobs et a/., 1978 Solomons and Russell, 1980). J. C. Smith et al, (1973) suggested that hepatic mobilization of vitamin A was impaired by zinc deficiency and their follow-up studies demonstrated a depression in liver and plasma RBP in the zinc-deficient rat compared to pair-fed controls (Brown et al., 1976 Smith et al., 1974). The depression was hypothesized to be the result of a depressed synthesis rather than an increased turnover of RBP. That preformed RBP is present in zinc-deficient rats was demonstrated by Carney et al. (1976) using labeled vitamin A. Zinc-deficient rats, whether or not they were also vitamin A-deficient, were able to mobilize over a short time span a small oral dose of vitamin A as well as could their pair-fed controls. Those animals deficient only in zinc excreted metabolites of the labeled vitamin in a similar quantitative manner as the pair-fed controls for 6 days postdosing. These data suggest that the release of retinol from retinyl ester stores, as well as a depressed RBP synthetic rate, contributed to low plasma levels of vitamin A in zinc deficiency. 

These data indicated that the increased level of RBP in serum after retinol injection mainly represented the release of RBP from an existing pool in the liver, rather than newly synthesized protein. Similarly, it was observed (Peterson et al., 1973) that actinomycin D did not block the retinol-stimulated mobilization of RBP from the livers of vitamin A-deficient rats. 

Third, as discussed earlier in this chapter, RBP plays an important role in the regulation of the mobilization of retinol from the liver stores and hence of its delivery to peripheral tissues. Thus, the rate of release of retinol from the liver appears to be controlled mainly by factors that regulate the rates of RBP synthesis and secretion by the liver. 

---