Retinyl esters storage

The overall metabolism of vitamin A in the body is regulated by esterases. Dietary retinyl esters are hydrolyzed enzymatically in the intestinal lumen, and free retinol enters the enterocyte, where it is re-esterified. The resulting esters are then packed into chylomicrons delivered via the lymphatic system to the liver, where they are again hydrolyzed and re-esterified for storage. Prior to mobilization from the liver, the retinyl esters are hydrolyzed, and free retinol is complexed with the retinol-binding protein for secretion from the liver [101]. Different esterases are involved in this sequence. Hydrolysis of dietary retinyl esters in the lumen is catalyzed by pancreatic sterol esterase (steryl-ester acylhydrolase, cholesterol esterase, EC 3.1.1.13) [102], A bile salt independent retinyl-palmitate esterase (EC 3.1.1.21) located in the liver cell plasma hydrolyzes retinyl esters delivered to the liver by chylomicrons. Another neutral retinyl ester hydrolase has been found in the nuclear and cytosolic fractions of liver homogenates. This enzyme is stimulated by bile salts and has properties nearly identical to those observed for... 

Figure 29-3. Chemical structures of important vitamin A species and the provitamin A carotenoid i-carotene. All-fra/w-fi-carolene (T) is the most important provitamin A carotenoid, which can be converted to all-fraws-retinal and then all-tram-retinol (If), which by definition is vitamin A. All-tram-retinol can be esterified with long-chain fatty acids to form retinyl ester (III), the storage form of vitaminA in the body.The active form of vitamin A in vision is 11-cts-retinal (TV).The transcriptionally active forms of vitaminA are all-tram-retinoic acid (V) and 9-cts-retinoic acid (VI). 13-cA-Retinoic acid (VII) has poor transcriptional regulatory activity but is used clinically as isotretinoin to treat skin diseases.

Structurally, vitamin A and many synthetic retinoids consist of a (3-ionone ring, a polyunsaturated polyene chain, and a polar end group. The polar end group can exist in several oxidation states, as retinol, retinal, or retinoic acid. Retinol and retinyl esters are the most abundant vitamin A forms found in the body (Blaner and Olson, 1994). Retinol can be esterified with long-chain fatty acids (mainly palmitate, oleate, and stearate) to form retinyl esters, which are the body s storage form of vitamin A. Retinol also can undergo oxidation to retinal, which can be oxidized further to retinoic acid. The active... 

Excessive intake of vitamin A (hyper-vitaminosis A), like too little intake, can result in adverse health consequences. Approximately 60%-80% of vitamin A is stored in the liver in hepatic stellate cells (also called Ito cells and fat-storing cells). Retinyl esters are the main storage form of vitamin A in the liver and are found in lipid droplets present in the hepatic... 

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). 

Although the major storage of vitamin A is in the liver (50% to 80% of the total body content), adipose tissue may contain 15% to 20% of total body vitamin A. Much of this is taken up from chylomicrons retinyl esters are hydrolyzed... 

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. ... 

All-trans retinol then diffuses out of the outer segments (rod or cone) and into the retinal pigmented epithelium (RPE). The diffusion of all-trans-retinol out of the outer segments and into RPE cells is facilitated by interstitial retinoid binding protein (IRBP), which is localized in the extracellular matrix of the retina (22). IRBP binds all-trans-retinol as it diffuses out of the outer segment cells and is believed to facilitate transport of aM-trans-retinol to the RPE cell. Additionally, RPE cells directly acquire retinol from serum as described earlier. In both cases, retinol in the RPE cell is rapidly esterified by LRAT in a lecithin-dependent mechanism (22). Retinyl esters provide both a mechanism of storage for the RPE cell and/or provide a substrate for the isomerization reaction (22). 

More than 90% of the body s supply of vitamin A is stored in the liver. The hepatic parenchymal cells are involved in its uptake, storage, and metabolism. Retinyl esters are transferred to hepatic fat-storing cells (also called Ito cells or lipocytes) from the parenchymal cells. The capacity of these fat-storing cells may determine when vitamin A toxicosis becomes symptomatic. During the development of hepatic fibrosis (e.g., in alcoholic liver disease), vitamin A stores in Ito cells disappear and the cells differentiate to myofibroblasts. These cells appear to be the ones responsible for the increased collagen synthesis seen in fibrotic and cirrhotic livers. 

In first central cleavage step, P-carotene (2) was converted to retinal (16) by P,P-carotene 15,15 -monooxygenase, and followed by retinol (18), retinyl esters of the storage forms such as retinyl acetate (22), retinol (18), retinal (16) by each enzyme, and finally retinoic acid (20) by retinal oxidase (Figure 5). 

When retinoids pass from the plasma membrane to intracellular sites of utilization and storage they must be transported through the cytosol. Both human and bovine RPE cytosols contain retinol and retinaldehyde in amounts equivalent to 1% of the retinyl esters in storage. Cytosol concentrations in these species are 3-7 [iM for retinaldehyde and 2-5 iiM for retinol. 

Fig. 16. Selective loss of I l-cis-retinyl ester (peak 2) in the RPE storage depots of eyes from a donor with dominantly inherited bilateral chorioretinal degeneration similar to retinitis pigmentosa (RPI37). (A) HPLC of retinyl esters from the affected tissue (B) HPLC of letinyl esters from normal tissue. Approximate amounts injected were 0.8 nmol for trace (A) and 19.5 nmol for trace (B). Peak I, 13-cis-retinyl palmitate and stearate peak 2, Il-cis-retinyl palmitate and stearate peak 3, not identified peak 4, all-rrons-retinyl palmitate and stearate peak S, all-frons-retinyl oleate. (From Bridges and Alvarez, 1982a.)...

Esters of retinol with long-chain fatty acids are a major storage form of vitamin A, espeeially in liver but also in other tissues. In some cases, it may be convenient to saponify the sample and assay total vitamin A as retinol in other cases, more information can be gained by analyzing the intact retinyl esters. Because all retinyl esters and retinol have identical molar absorptivity in a given solvent (123), retinyl palmitate can be used as a single quantitative standard for retinyl ester analysis if peak area (but not peak height) is used. 

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