Retinol, hepatic store

The interaction between alcohol and vitamin A is complex. They have overlapping metabolic pathways a similar 2-step process is involved in the metabolism of both alcohol and vitamin A, with alcohol dehydrogenases and acetaldehyde dehydrogenases being implicated in the conversion of vitamin A to retinoic acid. Alcohol appears to act as a competitive inhibitor of vitamin A oxidation. In addition, chronic alcohol intake can induce cytochrome P450 isoenzymes that appear to increase the breakdown of vitamin A (retinol and retinoic acid) into more polar metabolites in the liver, which can cause hepatocyte death. So chronic alcohol consumption may enhance the intrinsic hepatotoxicity of high-dose vitamin A. Alcohol has also been shown to alter retinoid homoeostasis by increasing vitamin A mobilisation from the liver to extrahepatic tissues, which could result in depletion of hepatic stores of vitamin A. ... 

Vitamin E stabilizes erythrocytes against lysis initiated by vitamin A vitro (Lucy and Dingle, 1964) and vivo (Soliman, 1972). Other reports demonstrated the conservation of hepatic stores of vitamin A by vitamin E (Davies and Moore, 1941) and confirmed by Cawthorne et al (1968). However, utilizations of 3-carotene in the presence of high intakes of tocopherol were blocked (Arnrich, 1978). The latter study suggested that tocopherol interacts with 3 carotene in the biochemical steps that occur just before the formation of retinol. 

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. 

Plasma vitamin A and RBP levels have been investigated in patients with cystic fibrosis of the pancreas (Smith et al., 1972 Knopfle et al., 1975 Palin et al, 1979). Plasma vitamin A and RBP levels have been found to be lower than normal in patients with cystic fibrosis, despite the administration of oral vitamin A supplements adequate to maintain normal hepatic stores. In one study (Smith et al., 1972), the plasma vitamin A transport system was studied in 43 patients with cystic fibrosis receiving oral supplements of vitamin A and in 95 normal control subjects of a similar age range. The mean plasma concentrations of vitamin A and RBP were significantly lower in the patients than in the controls. Moreover, in cystic fibrosis patients each component of the transport system failed to show the normal age-related rise. It is not known whether these abnormalities of the retinol transport system are primary or secondary features of cystic fibrosis the abnormalities may, however, play a role in the pathophysiology of the disease. 

RBP-bound retinol (RBP-ROH), the predominant form of retinoid in the fasting circulation, has a half-life of approximately 12 h [32]. RBP-ROH concentrations in well nourished Western populations range between 2 to 3 pmol/1 [2, 33]. Since retinol is released from hepatic stores together with RBP, and since RBP has one high affinity binding site for one molecule of retinol. 

Under conditions of either insufficient or excessive dietary retinoid intake an individual s circulating level of retinol is defended irrespective of the abundance of liver retinol stores, until liver stores reach some critical level beyond which the amount of circulating RBP-ROH is affected [35, 42, 52]. The regulatory factors responsible for establishing and maintaining this homeostatic set point within an individual are not well understood. In addition to any individual s normal serum retinol homeostatic set point, the critical level of hepatic stores also varies from one individual to another, and it has been suggested that it is influenced by non-retinoid factors such as the protein quality and quantity of the diet [34-36, 47, 53]. 

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. 

Pharmacokinetics Rapidly absorbed from the GI tract if bile salts, pancreatic lipase, protein, and dietary fat are present. Transported in blood to the liver, where it s metabolized stored in parenchymal hepatic cells, then transported in plasma as retinol, as needed. Excreted primarily in bile and, to a lesser extent, in urine. 

Altered vitamin A homeostasis, primarily manifested as decreased hepatic storage of vitamin A, is another established effect of PBBs in animals. Vitamin A is essential for normal growth and cell differentiation, particularly differentiation of epithelial cells, and some PBB-induced epithelial lesions resemble those produced by vitamin A deficiency. Because it is the primary storage site for vitamin A, the liver has a major role in retinol metabolism. Esterification of dietary vitamin A, hydrolysis of stored vitamin A, mobilization and release into the blood of vitamin A bound to retinol-binding protein, and much of the synthesis of retinol-binding protein occurs in the liver. 

When vitamin A stores are adequate, the liver secretes retinol bound to retinol-binding protein (RBP) into the circulation to provide tissues with a constant supply of vitamin A. In the circulation, the retinol-RBP complex is found bound to another circulating protein of hepatic origin, transthyretin (TTR). TTR also binds thyroid hormone and consequently plays a role in the transport of both vitamin A and thyroid hormone. The molecular size of the retinol-RBP complex is quite small, and the formation of the... 

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... 

Vitamin A is readily absorbed from the intestine as retinyl esters. Peak serum levels are reached 4 h after ingestion of a therapeutic dose. The vitamin is distributed to the general circulation via the lymph and thoracic ducts. Ninety percent of vitamin A is stored in the liver, from which it is mobilized as the free alcohol, retinol. Ninety-five percent is carried bound to plasma proteins, the retinol-binding protein. Vitamin A undergoes hepatic metabolism as a first-order process. Vitamin A is excreted via the feces and urine. Beta carotene is converted to retinol in the wall of the small intestine. Retinol can be converted into retinoic acid and excreted into the bile and feces. The elimination half-life is 9 h. 

Most retinoid reductions have been reported in response to organic contaminants, but other pollutants may affect storage levels. Lake trout (Salvelinus namaycush) inhabiting an area contaminated with iron-ore mine tailings had hepatic retinol and retinyl palmitate levels reduced by approximately 95%80. These fish also exhibited oxidative damage, providing indirect evidence that the loss of retinoid stores may be related to increased oxidative stress. 

In the liver, retinyl esters are hydrolyzed and reesterified. More than 95% of hepatic retinol is present as esters of long-chain fatty acids, primarily palmitate. In an adult receiving the RDA of vitamin A, a year s supply or more may be stored in the liver. 

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. 

Hepatic depletion of vitamin A stores is caused by chronic ethanol consumption (Bonjour, 1981). Night blindness suffered by alcoholics has been attributed to a low intake of vitamin A (McClain et aL, 1979). However, Sato and Lieber (1982) have demonstrated that ethanol depletes hepatic vitamin A stores in baboons and rats even when it is administered in combination with a nutritionally adequate diet. In addition, animals consuming ethanol in marginal diets were depleted more rapidly of vitamin A. No effect of ethanol intake on retinol binding protein or on serum vitamin A levels could be detected in these studies. Leo and Lieber (1982) found that hepatic vitamin A was depleted to one-fifth of normal levels in alcoholics with only moderate liver disease. Sato and Lieber (1982) observed that retinoic acid was more rapidly metabolized by the MFO system after chronic ethanol intake, and they postulated that vitamin A depletion was the result of MFO enzyme induction. 

Stored ester reserves. It should be noted that there are reports indicating that continued dietary supplementation of alcoholic cirrhosis (Mobarhan et al.y 1981) or cystic fibrosis (Fulton et al, 1982) patients with vitamin A in high doses does not always cause a sustained rise in plasma levels, though it may correct abnormalities in dark adaptation. These findings indicate that in these subjects with diseased livers, an impaired RBP synthetic rate is a major contributing factor to low circulating levels of retinol. Furthermore, alcohol per se has been shown in baboons and rats to increase the rate at which retinol is catabolized by hepatic tissue (Sato and Lieber, 1981) and some data from rats suggest that alcohol may potentiate the sensitivity of tissues to vitamin A, even in the presence of normal blood levels (Leo and Lieber, 1982). 

Zinc deficiency accompanied by a depression in plasma retinol has been noted in several studies. Some investigators have reported an increased liver vitamin A in several species of zinc-deficient animals (Stevenson and Earle, 1956 Saraswat and Arora, 1972 J. C. Smith et aL, 1973, 1976 Brown et aL, 1976 Jacobs et al., 1978 Carney et aL, 1976). There are also reports in humans in an association between lowered zinc, retinol, and RBP (Jacobs et a/., 1978 Solomons and Russell, 1980). J. C. Smith et al, (1973) suggested that hepatic mobilization of vitamin A was impaired by zinc deficiency and their follow-up studies demonstrated a depression in liver and plasma RBP in the zinc-deficient rat compared to pair-fed controls (Brown et al., 1976 Smith et al., 1974). The depression was hypothesized to be the result of a depressed synthesis rather than an increased turnover of RBP. That preformed RBP is present in zinc-deficient rats was demonstrated by Carney et al. (1976) using labeled vitamin A. Zinc-deficient rats, whether or not they were also vitamin A-deficient, were able to mobilize over a short time span a small oral dose of vitamin A as well as could their pair-fed controls. Those animals deficient only in zinc excreted metabolites of the labeled vitamin in a similar quantitative manner as the pair-fed controls for 6 days postdosing. These data suggest that the release of retinol from retinyl ester stores, as well as a depressed RBP synthetic rate, contributed to low plasma levels of vitamin A in zinc deficiency. 

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). 

Haskell MJ, Handelman GJ, Peerson JM, Jones AD, Rabbi MA, Awal MA, Wahed MA, Mahalanabis D, Brown KH (1997) Assessment of vitamin A status by the deuterated-retinol-dilution technique and comparison with hepatic vitamin A concentration in Bangladeshi surgical patients. Amer J Clin Nutr 66 61-1A Haskell MJ, Islam MA, Handelman GJ, Peerson JM, Jones AD, Wahed MA, Mahalanabis D, Brown KH (1998) Plasma kinetics of an oral dose of [ H4]retinyl acetate in human subjects with estimated low or high total body stores of vitamin A. Amer J Clin Nutr 68 90-95... 

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