Tocopherol transfer protein

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha (a), beta ((3), gamma (y) and delta (8), and four tocotrienols (also a, (3, y, and 8). a-Tocopherol is present in nature in only one form, RRR a-tocopherol. The chemical synthesis of a-tocopherol results in eight different forms (SRR, SSR, SRS, SSS, RSR, RRS, RSS, RRR), only one of which is RRR a-tocopherol. These forms differ in that they can be right (R) or left (S) at three different places in the a-tocopherol molecule. RRR a-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore the form of vitamin E found in the largest quantities in the blood and tissue. A protein synthesized in the liver (a-TTP alpha-tocopherol transfer protein) preferentially selects the natural form of vitamin E (RRR a-tocopherol) for distribution to the tissues. However, the mechanisms for the regulation of vitamin E in tissues are not known... 

A defect in an a-tocopherol-transfer protein causes a similar set of neurological symptoms. Oxidative damage may therefore be a component of this disease.4100... 

The affinities of a-tocopherol transfer protein for the other vitamers (relative to -tocopherol = 1, and based on competition with -toco-... 

Retention within tissues depends on intracellular binding proteins which, like the liver a-tocopherol transfer protein, have the highest affinity for RRR-a-tocopherol. The retention of a-tocopherol in tissues varies. In the lungs the vitamin has a half-life of 7.6 days, in liver 9.8 days, in skin 23.4 days, in brain 29.4 days, and in the spinal cord 76.3 days (Ingold et al., 1987). 

Patients who lack the hepatic tocopherol transfer protein (Section 4.2) and suffer from what has been called AVED (ataxia with vitamin E deficiency) are unable to export a-tocopherol from the liver in VLDL. 

HosomiA, Arlta M, Sato Y, Kiyose C, UedaT, Igarashi O, Aral H, and InoueK (1997) Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Letters 409,105-8. 

In intestinal mucosal cells, all vitamers of vitamin E cue incorporated into chylomicrons, and tissues take up some vitamin E from chylomicrons. Most, however, goes to the liver in chylomicron remnants, a -Tocopherol, which binds to the liver a-tocopherol transfer protein, is then exported in very low-density lipoprotein (VLDL) and is available for tissue uptake (Traber and Aral, 1999 Stocker and Azzi, 2000). Later, it appears in low-density Upoprotein (LDL) and high-density lipoprotein, as a result of metabolism of VLDL in the circulation. The other vitamers, which do not bind well to the a-tocopherol transfer protein, are not incorporated into VLDL, but are metabolized in the Uver and excreted. This explains thelower biological potency of the othervitcimers,despitesimilar, or higher, in vitro antioxidant activity. 

The affinities of a-tocopherol transfer protein for the other vitamers (relative to l l l -o -tocopherol = 1, and based on competition with RRR-oc-toco-pherol) are /8-tocopherol, 0.38 y-tocopherol, 0.09 5-tocopherol, 0.02 SRR-oc-tocopherol, 0.11 and a-tocotrienol, 0.09. As a result, whereas the hedf-life of a-tocopherol in the circulation is 48 hours, that of /3- emd y-tocopherol (emd the other vitamers) is only of the order of 13 to 15 hours. In patients with attixia and vitamin E deficiency caused by a genetic lack of a-tocopherol tremsfer... 

Shaw, H. M., and Huang, C. (1998) Liver alpha-tocopherol transfer protein and its mRNA are differentially altered by dietary vitamin E deficiency and protein insufficiency in rats. J Sutr 128, 2348-54. 

Gotoda, T, Arita, M., Arai, H Inoue, K., Yokota, T, Fukuo, Y., Yazaki, Y., and Yamada, N. (1995). Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the a-tocopherol-transfer protein, hi. Hngl. /, Mfd- 333, 1313-1318. 

The various forms of vitamin E are all absorbed by the gut in proportion to their abundance in the diet, where they appear in the chylomicrons. As the chylomicrons travel through the blood, the various forms of vitamin E are partly transferred to all the other types of lipoprotein particles. However, once vitamin E enters the liver, a-tocopherol is the only form that is preferentially packaged into the VLDLs (Traber, 1997). This preference seems to be a result of the activity of a-tocopherol transfer protein. This is a small protein that exists only in the cytoplasm of hepatocytes. 

A number of studies have suggested an association between elevated plasma vitamin E levels and reduced risk for cardiovascular disease (Bonithon-Kopp et ah, 1997 Gey, 1998 Rimm et ah, 1993 Stampfer et ah, 1993). The task of the nutritionist attempting to correlate vitamin intake with cardiovascular disease is complicated by the fact that different food oils contain different amounts of the various toco-pherols. Olive oil contains about 120 mg a-tocopherol/kg oil soybean oil (70 mg a-tocopherol and 900 mg y-tocopherol/kg) safflower oil (340 mg a-tocopherol and 35 mg y-tocopherol/kg) and wheat germ oil (1500 mg a-tocopherol and 800 mg y-tocopherol/kg) (Chase et ah, 1994 McLaughlin and Weihrauch, 1979). Most of the vitamin E present in blood plasma is a-tocopherol (rather than y-tocopherol, for example) because of the influence of a-tocopherol transfer protein. Most of the plasma vitamin E resides in the LDLs. A paradox seems to present itself where people who have elevated LDLs (and who are more at risk for cardiovascular disease) should also have elevated a-tocopherol (and possibly be at lesser risk for cardiovascular disease). This paradox can be avoided by expressing plasma a-to-copherol levels as a-tocopherol/cholesterol (Gey, 1998). 

Recent studies have shown that 2 S -configured tocopherols have no antioxidative effect in biological systems since they are not accepted as substrates by the a-tocopherol transfer protein (TTP), which is responsible for the transport of vitamin E into the tissue. On the other hand, the configuration of the stereogenic centers in the side chain seems to have no influence on the antioxidative activity. As a result, rac- exhibits only 50 % of the biological activity of RRR-1. Therefore, there is considerable interest in the development of an efficient process for the enantioselective synthesis of vitamin E (1) with special attention to the configuration of the stereogenic center C-2. 

Tocopherols and tocotrienols are believed to be absorbed to the same extent, but a tocopherol transfer protein with a specific affinity for a-tocopherol is considered responsible for the discrimination between the different E-vitamers and the selective incorporation of a-tocopherol into nascent, very-low-density lipoprotein (Hosomi et at., 1997). Other forms of vitamin E, which are discriminated during this process, are most likely excreted via the bile after shortening and carboxylation of their phytyl tails (Traber et al., 1998 Swanson et al., 1999). Recently, the biological importance of y-tocopherol has gained more attention. Because it is preferentially secreted from the liver into the small intestine via the bile duct, it may be superior to a-tocopherol in increasing the antioxidant status of digesta (Stone and Papas, 1997). When tissues are saturated with a-tocopherol, this E-vitamer is excreted via the bile to the same extent as the other vitamers (Kayden and Traber, 1993). 

Hosomi, A., Arita, M., Sato, Y., Kiyose, C., Ueda, T., Igarashi, O., Arai, H., and Inoue, K. 1997. Affinity for Alpha-Tocopherol Transfer Protein as a Determinant of the Biological Activities of Vitamin E Analogs. FEBS Lett. 409 105-108. 

RDA for vitamin E was increased in the year 2000 by 50% from 10 to 15 mg/day for adults by the U.S. Food and Nutrition Board.Most European reference intakes are related to the polyunsaturated fatty acid intake. The changes in the United States were accompanied by some debate, critics arguing that this amount could not be met by the usual North American diet. For infants up to 6 months, an AI of 4mg/day was proposed, for infants 7 to 12 months an AI of 5mg/day and the RDA for children 1 to 18 years was set at 6 to 15 mg/day, dependent upon age. Another departure in the newer recommendations was that the daily requirement he met by RRR-a-tocopherol alone as the other forms of vitamin E are not converted to a-tocopherol and are poorly recognized by the a-tocopherol transfer protein in the liver. 

Schuelke M, Mayatepek E, Inter M, Becker M, Pfeiffer E, Speer A et al. Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency. J Pediatr 1999 134 240-4. 

Vitamin E deficiency occurs due to genetic defects in the formation of hepatic a-tocopherol transfer protein. This transport protein plays a central role in the liver and one of its functions is to facilitate incorporation of a-tocopherol into nascent very low density lipoproteins (VLDLs). Since there are no specific transport proteins for vitamin E in plasma, the delivery of vitamin E to the tissues is primarily mediated by VLDL-LDL transport mechanisms (Chapter 20). Thus, deficiency of hepatic a-tocopherol transport protein causes low plasma levels of vitamin E with impairment of delivery to the tissues. Patients with the transport protein deficiency exhibit peripheral neuropathy and ataxia. Early and vigorous vitamin E supplementation in patients with neurological symptoms and with low plas-mal levels of vitamin E has yielded therapeutic benefits. 

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