Chylomicron retinol

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. 

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. 

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. 

Dietary retinol is transported as retinyl esters in chylomicrons. 

Retinol A. can be enzymically formed from retinoic acid. B. is transported from the intestine to the liver in chylomicrons. C. is the light-absorbing portion of rhodopsin. D. is phosphorylated and dephosphorylated during the visual cycle. E. mediates most of the actions of the retinoids. Correct answer = B. Retinyf esters are incorporated into chylomicrons. Retinoic acid cannot be reduced to retinol. Retinal, the aldehyde form of retinol, is the chromophore for rhodopsin. Retinal is photoisomerized during the visual cycle. Retinoic acid, not retinol, is the most important retinoid. 

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. 

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). 

A variety of other tissues synthesize RBP this provides a mechanism for return to the liver of retinol in excess of requirements that has heen taken up from chylomicrons hy the action of Upoprotein lipase. Because these tissues do not synthesize transthyretin, the hinding of holo-RBP to transthyretin must occur in the circulation after release. 

The Relative Dose Response (RDR) Test The RDR test is a test of the ahUity of a dose of vitamin A to raise the plasma concentration of retinol several hours later, after chylomicrons have heen cleared from the circulation. What is being tested is the ahUity of the liver to release retinol into the circulation. In subjects who are retinol deficient, a test dose will produce a large increase in plasma retinol, because of the accumulation of apo-RBP in the liver in deficiency (Section 2.2.3). In those whose problem is due to lack of RBP, then little of the dose will be released into the circulation. An RDR greater than 20% indicates depletion of liver reserves of retinol to less than 70 /rmol per kg (Underwood, 1990). 

Ito cells (T. Ito, 1951) are also known as fat-storing cells, hepatic stellate cells or lipocytes. These long-lived cells, 5-10 im in size with long thin strands, lie in Disse s space (s. figs. 2.8, 2.9) and contain numerous cytoplasmic fat droplets as well as an abundance of vitamin A (= retinol ester). The retinol esters of the chylomicrons are absorbed by the hepatocytes and hydrolyzed into retinol. The latter is either passed to the blood by means of RBP or transported to Ito cells and stored. In the fat droplets of Ito cells, about 75% of the liver retinoids are present in the form of retinol esters. These fat droplets are characteristic of Ito cells they represent vacuolized... 

Retinol is esterified to palmitic acid in the intestinal mucosa and secreted as components of chylomicrons into the lymphatic system and through blood stored in liver. 

The uptake of chylomicron remnants by the liver results in delivery of retinol to this organ for storage as a lipid ester within lipocytes. 

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. 

Vitamin E is absorbed from the gut with the aid of bile salts. The vitamin is not esterified to a fatty acid during absorption, as is the case with cholesterol and retinol. Vitamin E is transported to the bloodstream in chylomicrons and distributed to the various tissues via the lipoproteins. 

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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