Chylomicron retinol metabolism

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. 

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... 

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. ... 

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.

FIG. 6. Compartmental model proposed by Green et al. (1993) for liver and whole-body vitamin A metabolism. Compartment 11 is plasma retinol. PC, parenchymal cells NPC, nonparenchymal cells (assumed here to be perisinusoidal stellate cells) ROH, retinol RE, retinyl esters CM, chylomicrons. 

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. 

The liver plays the major role in the body in the uptake and metabolism of newly absorbed retinol (retinyl esters). Thus, retinyl esters appear to remain almost completely with the hydrophobic core of the chylomicron during its extrahepatic conversion to a remnant particle, and then to be taken up by the liver in association with the chylomicron remnant. A quantitative and detailed study of these processes was reported by Goodman et al. (1965). Chylomicrons containing newly absorbed labeled retinol (93% as retinyl esters) were injected intra-... 

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. 

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