Liver retinyl ester

Table 2.3 Biochemical Indices of Vitamin A Status Liver Retinyl Esters (as Retinol) (j mol/kg...

In the liver, retinyl esters are hydrolyzed and reesterified. More than 95% of hepatic retinol is present as esters of long-chain fatty acids, primarily palmitate. In an adult receiving the RDA of vitamin A, a year s supply or more may be stored in the liver. 

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-... 

When some of the model parameters lack sufficient statistical certainty, the investigator may search the scientific literature for relevant information and use it to set constraints on the numerical values of some parameters of the model. Several statistical constraints were added in constructing the model shown in Fig. 3. The FTC of retinyl ester from the chylomicron retinyl ester to the fast turnover liver retinyl ester compartment was constrained to be inside the range of two statistical deviations of 60 36/day (mean ... 

Fast turnover liver 0-carotene Fast turnover liver retinyl ester 0.091 0.088 0.405... 

Fast turnover liver retinyl ester Slow turnover liver retinyl ester 2.60 0.22 13.2... 

Fast turnover liver retinyl ester Retinol-binding protein retinol 2.74 0.11 13.9... 

Retinol-binding protein retinol Fast turnover liver retinyl ester 2.99 0.21 26.4... 

Chylomicron retinyl ester Fast turnover liver retinyl ester 122.7 0.077 0.297... 

Note FTC is the fractional transfer coefficient its units are per day. FSD is fractional standard deviation of FTC. Flow (rates) are /onol/day. Ineveisble loss of -carotene (fecal) = 240 - FTC from GIT to GIT delay compartment. FTC from chylomicron retinyl ester to fast turnover liver retinyl ester = 60 36. Values apply to model in Figure 3. Reprinted with permission from Novotny et al. (1995). 

Both intact carotenoids and their apolar metabolites (retinyl esters) are secreted into the lymphatic system associated with CMs. In the blood circulation, CM particles undergo lipolysis, catalyzed by a lipoprotein lipase, resulting in the formation of CM remnants that are quickly taken up by the liver. In the liver, the remnant-associated carotenoid can be either (1) metabolized into vitamin A and other metabolites, (2) stored, (3) secreted with the bile, or (4) repackaged and released with VLDL particles. In the bloodstream, VLDLs are transformed to LDLs, and then HDLs by delipidation and the carotenoids associated with the lipoprotein particles are finally distributed to extrahepatic tissues (Figure 3.2.2). Time-course studies focusing on carotenoid appearances in different lipoprotein fractions after ingestion showed that CM carotenoid levels peak early (4 to 8 hr) whereas LDL and HDL carotenoid levels reach peaks later (16 to 24 hr). 

Tanumihardjo, S. A., H. C. Furr, O. Amedee-Manesme, and J. A. Olson. 1990. Retinyl ester (vitamin A ester) and carotenoid composition in human liver. Int. J. Vitam. Nutr. Res. 60 307-313. 

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... 

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. 

These results show that retinyl esters in respiratory epithelium and in alveolar cells form a pool of vitamin A, which can be used physiologically by the tissue. The formation of retinol and at least RA from retinyl esters is strictly controlled. So far an unphysiological formation of RA and a subsequent toxicity seems not possible. Retinyl esters, however, are biochemically inert with respect to gene expression or vitamin A activity as long as they are not hydrolyzed. Consequently, the inhalative application, especially in cases of insufficient lung development, could represent a true alternative. The oral contribution is hardly successful because of the poor RBP s)mthesis of the liver and the lack of availability of a parenteral solution is currently not available. 

The obtained results confirm earlier findings where vitamin A-deficient rats were used to prove the uptake of retinyl esters into lung, liver, kidney, and plasma after inhalation thereof (Biesalski, 1996). However, long-term topical administration of high vitamin A concentrations is a well-established therapy in atrophic rhinitis, rhinitis sicca, and metaplastic changes in the nasal or ocular epithelium (Deshpande et ah, 1997 Simm, 1980). The application leads to the normalization of mucous membranes and reappearance of a normal function with no side effects. 

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. 

Retinyl esters and the P-carotene are incorporated into chylomicrons and taken up mainly by hepatocytes. In the liver retinol may be stored in stellate cells as retinyl esters, oxidized to retinoic acid or liberated into cells bound to retinol-binding proteins (RBP). All E retinoic acid and its 9Z isomer have an affinity for nuclear receptors. They activate the transcription and bind as dimers to specific nucleotide sequences, present in promoters of target genes. 

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... 

Additional noteworthy applications of CEC include natural products such as the plant flavonoids hesperetin and hesperidin [160], anthraquinones extracted from rhubarb and from Chinese medicine [161], and heterocyclic compounds present in oils of bergamot, mandarin, and sweet orange [162], The CEC analysis of retinyl esters has been investigated by Roed et al. in nonaqueous mode for the separation of liver extracts of arctic seal [163]. Carotenoid isomers were also separated on C30 stationary phases by nonaqueous CEC [164]. It was found that CEC offered increased resolution compared to HPLC, and in CEC... 

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). 

Studies in vitamin A replete animals suggest that most of the retinol is transferred from hepatocytes to the perisinusoidal stellate cells of the liver. Here, it is again esterified by LRAT to form mainly retinyl palmitate (76% to 80%), with smaller amounts of stearate (9% to 12%), oleate (5% to 7%), and linoleate (3% to 4%). The stellate cells contain 90% to 95% of hepatic vitamin A, as cytoplasmic lipid droplets that consist of between 12% to 65% retinyl esters (Batres and Olson, 1987). Studies with [ C]retinyl palmitate show that much of the recently ingested retinol appears more or less immediately in the... 

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 test requires two samples of blood, taken before and 5 hours after the test dose of retinol. A modified RDR test involves giving a test dose of dehydroretinol, then determining the ratio of dehydroretinokretinol in a single plasma sample taken 30 hours later. Again, because of the accumulation of RBP in the liver in deficiency and because in deficiency there is less dilution of dehydroretinol with liver pools of retinyl esters, the ratio is inversely proportional to the liver stores of retinol (Tanumihardjo et al., 1987). 

As the intake of vitamin A increases, there is an increase in the excretion of metabolites in bile, once adequate liver reserves have been established. However, the biliary excretion of retinol metabolites reaches a plateau at relatively low levels, and it seems likely that this explains the relatively low toxic threshold (Olson, 1986). Vitamin A intoxication is associated with the appearance of both retinol and retinyl esters bound to albumin and in plasma lipoproteins, which can be taken up by tissues in an uncontrolled manner the amount of circulating retinol bound to RBP does not increase. Retinol has a membrane lytic action it was noted in Section 2.2.2.3 that one of the functions of RBP binding seems to be to protect tissues against retinol, as well as to protect retinol against oxidation (Meeks et al., 1981). 

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