Chylomicron retinyl esters

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... 

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 ... 

SD) in order to correspond with the known half-life of chylomicron retinyl esters (IS 10 min) in healthy adult men (Cortner et aL, 1987). Also, the model intestinal absorption of j8-carotene was constrained to be inside the range of two statistical deviations of 15 4.5% based on a j8-carotene balance study (Bowen et aL, 1993) in which 4.3 0.8 punol of a 28-jiunol dose of /3-carotene was absorbed in healthy subjects. Each of these constraints was achieved by including additional data points in the model. Finally, the irreversible loss of retinol from the model system was constrained to a minimum value of 0.7 pimol/day based on the rate of vitamin A depletion in humans (Sauberlich et aL, 1974). These additions to the model provided good statistical certainty on all model parameters, as the FSDs of the FTCs were <25% (see Table I). 

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). 

Dietary retinyl esters are hydrolyzed in the intestinal lumen, and the resulting retinol is absorbed into the mucosal cell. Retinol in the mucosal cell (newly absorbed or newly synthesized from carotene) is reesterified with long-chain, mainly saturated fatty acids the retinyl esters, in association with chylomicrons, are then transported via the lymph into the general circulation. After entry into the vascular compartment, chylomicrons are metabolized in extrahepatic tissues by the lipolytic removal of much of the chylomicron triglyceride. The chylomicron remnant thus formed is a smaller and cholesterol-rich particle that contains essentially all the chylomicron retinyl esters and is removed from the circulation almost entirely by the liver. 

After uptake of the chylomicron retinyl esters, hydrolysis and reesterification occur in the liver. The resulting retinyl esters (predominantly retinyl palmitate) are stored in the liver and can be mobilized as needed in a highly regulated process. Vitamin A mobilization from hepatic retinyl ester stores takes place as the free alcohol retinol bound to a specific plasma transport protein retinolbinding protein (RBP). 

Much information is available about the metabolism of chylomicron cholesteryl esters taken up by the liver in association with the chylomicron remnant. This information may be relevant to the issue of chylomicron retinyl ester metabolism in the liver, about which much less direct information is on hand. Hepatic uptake of chylomicron cholesteryl esters occurs without hydrolysis of the cholesteryl esters (Goodman, 1965 (Juarfordt and Goodman, 1967 Stein et al., 1969). In studies with chylomicrons containing doubly labeled cholesteryl esters injected intravenously into rats, Quarfordt and Goodman (1967) observed that 80-90% of the chylomicron cholesteryl esters were removed by the liver without hydrolysis. In the liver, the newly absorbed cholesteryl esters underwent slow but extensive hydrolysis, to the extent of about 60% after 1 h and about 85-90% after 3.5 h. Subsequent to hydrolysis, most of the labeled free cholesterol slowly left the liver and was extensively redistributed in die body. Thus, 24 h later, only 20-28% of the labeled cholesterol found in the entire animal body was present in the liver. Since newly absorbed retinol, which is retained in the liver, is only mobilized slowly (see below), it is clear that following ester hydrolysis the hepatic metabolism of chylomicron cholesterol and retinol diverge in a major way. 

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. 

In humans, molar concentrations of chylomicron retinyl esters can exceed those of retinol-RBP by 3- to 4-fold during the 3 to 6 h following consumption of a bolus test dose of retinol [8] or of a retinol-rich meal [7]. For healthy humans, postprandial clearance of chylomicron retinoids normally occurs within 6 to 8 h [4, 8]. However, in some disease states in which clearance of postprandial lipids is delayed, the rate of chylomicron retinoid clearance can be much slower than that of healthy individuals. Chylomicron retinoid clearance in rats and mice is more rapid than in humans, with circulating chylomicron retinyl ester levels reaching a maximum within 2 to 4 h after consumption of retinol [30]. 

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. 

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. 

Dietary retinol is transported as retinyl esters in chylomicrons. 

Within the enterocyte, retinol is bound to cellular retinol binding protein (CRBP 11) and is esterified by lecithin retinol acyltransferase (LRAT), which uses phosphatidylcholine as the fatty acid donor, mainly yielding retinyl palmitate, although small amounts of stearate and oleate are also formed. At unphysiologically high levels of retinol, when CRBP 11 is saturated, acyl coenzyme A (CoA) retinol acyltransferase (ARAT) esterifies the free retinol that accumulates in intracellular membranes. Then the retinyl esters enter the lymphatic circulation and then the bloodstream (in chylomicrons), together with dietary lipid and carotenoids (Norum et al., 1986 Olson, 1986 Blomhoff et al., 1991 Green et al., 1993 Harrison and Hussain, 2001). 

A small proportion of dietary retinol is oxidized to retuioic acid, which is absorbed into the portal circulation and bound to serum albumin. Some retinyl esters are also transferred into the portal circulation. Patients with abeta-lipoproteinemia, who are unable to synthesize chylomicrons, can nevertheless maintain adequate vitamin A status if they are provided with relatively high intakes of retinol. 

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). 

The cleavage of p-carotenc to form retinal, followed by the reduction of retinal to retinol, is shovk n in Figure 9.41, The refinoJ is converted to the retinyl ester, packaged in chylomicrons, and exported in the lymphatic system. 

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. ... 

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