Retinyl esters secretion

In intestinal cells, carotenoids can be incorporated into CMs as intact molecules or metabolized into mainly retinol (or vitamin A), but also in retinoic acid and apoc-arotenals (see below for carotenoid cleavage reactions). These polar metabolites are directly secreted into the blood stream via the portal vein (Figure 3.2.2). Within intestinal cells, retinol can be also esterified into retinyl esters. 

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). 

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... 

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). 

In our studies, we have administered tritium-labeled vitamin A in one of its two physiological plasma transport vehicles (associated with either retinol-binding protein or chylomicrons) so that tracer data can be extrapolated to the vitamin A compounds of interest (retinol, retinyl esters, and metabolites). To prepare pH]retinol in its plasma transport complex (Green and Green, 1990b), vitamin A-depleted rats are used as donors to maximize hepatic secretion of the labeled vitamin on acciunulated liver apoRBP. pH]Retinol or pH]retinyl acetate in an emulsion with Tween 40 is administered intravenously to donor rats and blood is harvested 100 min later when plasma radioactivity is maximal. Plasma is isolated and stored under a nitrogen atmosphere at 4°C plasma is used for in vivo studies within 23 days. 

HJvitamin A-labeled chylomicrons, values for only 3 of the 24 fractional transfer coefficients had to differ to fit the two data sets. Thus we speculate that these three parameters [L(5,6), L(3,4), and L(22,5) Fig. 6] are sensitive to vitamin A status. This makes physiological sense since these parameters reflect retinyl ester hydrolysis and stellate cell retinol secretion. 

To mobilize liver stores, our model predicts that retinyl esters in PC or SC are hydrolyzed and the resulting retinol is transferred to the slower turning-over retinol pool (compartment 5 in SC and 3 in PC), presumably bound to CRBP. It is then transferred to an exocytosis compartment. Our kinetic data indicate that this retinol does not need to go back to PC before secretion into plasma. Maybe apoRBP can interact with RBP receptors and equilibrate retinol between intraceUular CRBP and plasma RBP. If so, this is an excellent example of homeostatic control since cellular retinol pools are in equilibrium with plasma retinol. If an exchange of retinol between apoC P and apoRBP is shovm to be mediated by a specific membrane protein, the protein should perhaps be named a retinol transporter, rather than an RBP receptor (Blomhoff et aL, 1991). 

Retinol within the mucosal cell is largely reesterified with long-chain fatty acids. The retinyl esters are then incorporated, together with other lipids and with apolipoproteins, into chylomicron particles that are secreted from the cell into the lymph. 

Retinyl esters are secreted from absorptive cells mainly in the hydrophobic... 

Repletion of retinol-deficient rats can also be effectively achieved by the intravenous injection of retinol dispersed in a 20% Tween 40 solution (Smith et al., 1980 Fig. 4). Such an injection produces a rapid, dose-related increase in the serum concentration of RBP. The changes in serum RBP levels seen after the injection of retinol in a 20% Tween 40 solution closely resembled those previously seen after the injection of vitamin A (retinyl esters) in association with lymph chylomicrons. However, the amount of retinol required to stimulate the secretion of a given amount of RBP from the liver was about two to three times that required when retinol (retinyl esters) was injected in chylomicrons. As discussed by Smith et al. (1980), this quantitative difference is probably due to differences in the tissue distribution pattern of retinol when injected in the Tween 40 solution, compared to its administration in the form of chylomicrons. 

Retinyl ester stored in the liver must be hydrolyzed before the retinol can be mobilized from the liver as the retinol-RBP complex. Information is needed as to whether or not the processes of retinyl ester hydrolysis and of RBP production and secretion might, under some circumstances, be coordinated in some way. The question to be asked is whether or not the hydrolysis of retinyl esters might at times serve as one of the regulatory steps in the overall process of retinol mobilization from the liver. Information available about the enzymatic hydrolysis of retinyl esters in liver is reviewed in Chapter 7. 

Retinyl esters formed in the intestinal mucosa enter the lymphatic circulation, in chylomicrons (section 5.6.2.1) together with dietary lipid and carotenoids. Tissues can take up retinyl esters from chylomicrons, but most remains in the chylomicron remnants that are taken up by the liver. Here the esters are hydrolysed, and the vitamin may be either secreted from the liver bound to retinol-binding protein or transferred to stellate cells in the liver, where it is stored as esters in intracellular lipid droplets. 

Together with triglycerides, cholesteryl esters, phospholipids and other dietary lipids, dietary retinol is incorporated as retinyl ester into chylomicron particles that are secreted by the en-... 

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