Chylomicron 3-carotene

FIGURE 3.2.2 Metabolic pathways of carotenoids such as p-carotene. CM = chylomicrons. VLDL = very low-density lipoproteins. LDL = low-density lipoproteins. HDL = high-density lipoproteins. BCO = p-carotene 15,15 -oxygenase. BCO2 = p-carotene 9, 10 -oxygenase. LPL = lipoprotein lipase. RBP = retinol binding protein. SR-BI = scavenger receptor class B, type I. 

Borel, P. et al.. Chylomicron (3-carotene and retinyl palmitate responses are dramatically diminished when men ingest (3-carotene with medinm-chain rather than long-chain triglycerides, J. Nutr, 128, 1861, 1998. 

C. Gartner, W. Stahl, and H. Sies, Preferential increase in chylomicron levels of the xanthophylls lutein and zeaxanthin compared to beta-carotene in the human, Int. J. Vitam. Nutr. Res. 66 (1996) 119-125. 

W. Stahl, W. Schwarz, J. von Laar, and H. Sies, All-trans beta-carotene preferentially accumulates in human chylomicrons and very low density lipoproteins compared with the 9-cis geometrical isomer, J. Nutr. 125 (1995)2128-2133. 

Tyssandier, V. et al. (2002). Vegetable-home lutein, lycopene, and beta-carotene compete for incorporation into chylomicrons, with no adverse effect on the medium-term (3-wk) plasma status of carotenoids in humans. Am. J. Clin. Nutr. 75(3) 526-534. 

In the enterocyte, provitamin A carotenoids are immediately converted to vitamin A esters. Carotenoids, vitamin A esters, and other lipophilic compounds are packaged into chylomicrons, which are secreted into lymph and then into the bloodstream. Chylomicrons are attacked by endothelial lipoprotein lipases in the bloodstream, leading to chylomicron remnants, which are taken up by the liver (van den Berg and others 2000). Carotenoids are exported from liver to various tissues by lipoproteins. Carotenes (such as (3-carotene and lycopene) are transported by low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL), whereas xanthophylls (such as lutein, zeax-anthin, and (3-cryptoxanthin) are transported by high-density lipoproteins (HDL) and LDL (Furr and Clark 1997). 

Dietary fats are required for carotenoid uptake by intestinal cells. Fats have an important role in the continuation of the process of carotenoid absorption, because the human intestine is incapable of secreting significant quantities of chylomicrons into the bloodstream in the absence of fats (Ornelas-Paz and others 2008b). Some studies have suggested that at least 5 g/day of dietary fat are required for suitable (3-carotene absorption (West and Castenmiller 1998), whereas others suggested the consumption... 

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. 

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. 

In the intestinal mucosal cells, /3-carotene is cleaved via an oxygenase (an enzyme that introduces molecular 02 into organic compounds) to frans-retinal (aldehyde form of trans-retinol, as shown in Table 6.2), which in turn is reduced to frans-retinol, vitamin Av Retinol is then esterified with a fatty acid, becomes incorporated into chylomicrons, and eventually enters the liver, where it is stored in the ester form until it is required elsewhere in the organism. The ester is then hydrolyzed, and vitamin Ax is transported to its target tissue bound to retinol-binding protein (RBP). Since RBP has a molecular weight of only 20,000 and would be easily cleared by the kidneys, it is associated in the bloodstream with another plasma protein, prealbumin. 

As discussed in Section 2.2.2.2, only a relatively small proportion of carotene undergoes oxidation in the intestinal mucosa, and a significant amount of carotene enters the circulation in chylomicrons. Novotny and coworkers (1995) reported a study in one subject given an oral dose of pff]/3-carotene dissolved in oU 22% was absorbed - 17.8% as carotene and 4.2% as retinoids. Their results suggest that nonintestinal carotene dioxygenase is important in retinoid formation, because there was a late disappearance of labeled carotene from the circulation and the appearance of labeled retinoids. 

The cleavage of P-carotene to form retinal, followed by the reduction of retinal to retinol, is shown in Figure 9.41. The retinol is converted to the retinyl ester, packaged in chylomicrons, and exported in the lymphatic system. 

Fig. 2. Tissue distribution and metabolism of retinoids in fish. Dietary carotenoids (e.g. /3-carotene (/3C)) and retinyl esters (e.g. retinyl palmitate (RP)) are converted into retinol (Rol) in the lumen of the gut. Retinol is then re-esterified and packaged into chylomicrons and transported to the portal circulation. When required elsewhere, stored retinyl esters (e.g. RP) in the liver are hydrolyzed to retinol and transported in the blood bound to the retinol-binding protein (RBP). Retinol is converted in target tissues to RA, RP or retinal (Ral). RA may exert its effects locally, or be returned to the circulation and transported throughout the body bound to albumin. RA can then be sequestered in other tissues.

In this conceptual model, a single oral dose of/8-carotene passes through a stomach compartment and enters an intestine compartment, where it is prepared for absorption. During absorption, intact /3-carotene is absorbed and transferred to a plasma chylomicron (which become remnants by removal of triglycerides) compartment from where it transfers to a liver compartment and is rereleased into a plasma lipoprotein compartment (Krinsky et ai, 1958 Cornwell et al, 1962 Clevidence and Bieri, 1993) for delivery to an extrahepatic compartment. Eventually /8-carotene metabolites are lost irreversibly from the extrahepatic tissue compartment (EHT) into plasma and returned to liver for disposal probably via bile or other irreversible loss. Since plasma lipoproteins are taken up by liver (Danger et al, 1972), /3-carotene in the lipoprotein compartment would be recycled back to liver, even several times this pathway is included in the model. 

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-... 

Once the delay and enterocyte compartments were added, the initial slope (rise) in the plasma j3-carotene-dg concentration-time curve was still shallower than the rise observed with the experimental observations. Reasoning that the initial sharp rise in the plasma j8-carotene-dg data represented chylomicron /3-carotene rapidly entering the plasma, we increased the FTC of /3-carotene from the enterocyte compartment to the plasma chylomicron compartment until the initial slope (rise) in the model-predicted plasma -carotene-dg concentration-time curve matched the rise that occurred in the experimental observations as shown in Fig. 5, left panel. 

Adding the delay and enterocyte compartments and increasing the FTC of /3-carotene from the enterocyte compartment to the plasma chylomicron compartment produced an intermediate model that predicted the initial rise in plasma /3-carotene-dg concentration very well. At the same time, this version of the model predicted a single peak with a shoulder (Fig. S, left panel) for the plasma /3-carotene-dg concentration-time curve instead of the two peaks indicated by the experimental observations. This discrepancy was resolved by increasing the FTC for /3-carotene from the plasma chylomicron compartment to the liver /3-carotene compartment (Fig. 5, right panel). The two /3-carotene peaks were not resolved when this FTC was too small (see left panel). 

It must be realized, however, that the data used to build a particular compartmental model may not always provide sufficient statistical certainty of a given parameter s value. Because retinol-d4 and retinyl-d4 ester were not measured individually in the plasma after the subject ingested the /3-carotene-dg, we were unable to determine with statistical certainty the FTCs specifically for retinyl ester. Movement of retinyl ester from the enterocyte into the plasma was highly correlated with its removal from the plasma into the liver via chylomicron remnant. Therefore, the FTCs describing movement of retinyl ester from the enterocyte to the plasma and from the plasma to the liver could be increased simultaneously without compromising the model s prediction of the experimental observations. 

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 /3-carotene Fast turnover liver 0-carotene -34.76 0.059 1.24... 

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). 

The predicted chylomicron retinyl-d4 ester curve is characterized by a sharp peak similar to that of the /3-carotene-dg, again in accord with the expected rapid clearance of chylomicrons foUowing a meal. The predicted plasma retinol-binding protein-retinol-d4 curve shows an initial rise and fall, then a sustained level of retinol-d4 after the /3-carotene-dg dose. This is very similar in shape to that seen when the same subject ingested retinyl-d4 acetate in a previous experiment (Song et oL, 1995). The sustained level of retinol-d4 is a result of the slow release of retinoid into the plasma from... 

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